Tocilizumab in the Treatment of Refractory Polymyositis and Dermatomyositis
Condition: Dermatomyositis; Polymyositis
MeSH terms: Dermatomyositis; Polymyositis
Intervention: tocilizumab; placebo
Intervention description: given at a dose of 8mg/kg by IV infusion every 4 weeks at 6 time points (Visits 1, 2, 3, 4, 5 and 6).; given by IV infusion every 4 weeks at 6 time points (Visits 1, 2, 3, 4, 5 and 6).
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 36.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: dermatomyositis; polymyositis; tocilizumab; Actemra

Summary:

      The purpose of this multi-center pilot study is to determine if the drug tocilizumab
      (Actemra) is effective in the treatment of patients with refractory adult polymyositis (PM)
      and dermatomyositis (DM).
    

Eligibility criteria:

        Inclusion Criteria:

        Patients will be included in the trial based on the following criteria:

          1. Definite or probable polymyositis (PM )or dermatomyositis (DM) by the criteria of
             Bohan and Peter (as modified by IMACS) in adults over the age of 18. We will also
             allow enrollment of juvenile dermatomyositis(JDM) patients (considered to have DM)
             over the age of 18 who otherwise meet the inclusion criteria stipulated below.

          2. Subjects must either have the classic rash(es) of DM (heliotrope, Gottron sign or
             Gottron papules), possess one of the myositis-associated autoantibodies (e.g.
             anti-synthetase, anti-signal recognition particle (anti-SRP), anti-Mi-2, anti-PM-Scl,
             transcription intermediary factor 1-γ (anti TIF1-γ etc.), or have the diagnosis of PM
             agreed upon by a 3-member Adjudication Committee consisting of a rheumatologist,
             neurologist and neuromuscular pathologist.

          3. Refractory myositis patients are defined (see Section 3.1.1) as having failed (or
             considered intolerant to) an adequate course of glucocorticoids or having failed
             glucocorticoids and at least one other immunosuppressive (IS) or immunomodulatory
             agent (e.g. methotrexate, azathioprine, cyclosporine, tacrolimus, mycophenolate
             mofetil, cyclophosphamide, Intravenous immunoglobulin (IVIg), anti-tumor necrosis
             factor (anti-TNF) agents, and rituximab).

          4. Subjects with an Manual muscle score (MMT-8) score ≤ 66 (see Appendix B) must also
             have at least 2 other core set measures meeting the criteria listed below.

          5. Subjects with an MMT-8 score > 66 must have at least 3 other core set measures meeting
             the criteria listed below and a global extramuscular visual analog score (VAS) score
             on the Myositis Disease Activity Assessment Tool ( MDAAT) ≥ 5cm on a 10cm scale.

          6. Criteria for core set measures for study entry:

               1. Patient global VAS with a minimum value of 2.0cm on a 10cm scale.

               2. MD global VAS with a minimum value of 2.0cm on a 10cm scale.

               3. Health Assessment Questionnaire (HAQ) disability index with a minimum value of
                  0.25

               4. Elevation of at least one of the muscle enzymes (Creatine kinase (CK), aspartate
                  aminotransferase (AST), alanine transaminase (ALT), aldolase, Lactate
                  dehydrogenase (LDH) at a minimum level of 1.3x the upper limit of normal (ULN).

               5. Global extramuscular disease activity score with a minimum value of 1.0cm on a
                  10cm VAS scale on the Myositis Disease Activity Assessment Tool (MDAAT).

          7. If on prednisone, the dose must be stable for 4 weeks prior to the screening visit.
             Tapering of the prednisone dose will only be allowed after the subject meets the
             Definition of Improvement (DOI) or if safety/toxicity issues supervene.

               1. Prednisone Tapering: Prednisone should be held constant without tapering or
                  escalation (unless there is a serious adverse event or disease flare) until the
                  subject has achieved the DOI. Then, tapering of prednisone may commence using a
                  schedule approximating a 20-25% taper of the existing dose every 4 weeks based on
                  the clinical judgment of the clinical site investigator. Prednisone tapering
                  using the aforementioned guidelines can be commenced at any time if: (a) the
                  patient achieves the DOI or (b) there are complications or circumstances that, in
                  the clinical site investigator's opinion, necessitate the tapering of
                  corticosteroids.

               2. Prednisone at Entry: It is also recommended that patients be on less than
                  1mg/kg/day of prednisone at study entry.

               3. Prednisone Dosing During Flare: If in the clinical site investigator's opinion
                  there are complications or worsening of disease that necessitate an increase in
                  the prednisone dose then the smallest reasonable increase should be considered.

          8. If an immunosuppressive (IS) agent was discontinued prior to the screening visit there
             may be a washout as stipulated below or individualized according to the patients
             treating physician:

               1. 4 week washout for methotrexate

               2. 8 week washout for any other IS agent (e.g. azathioprine, cyclosporine,
                  tacrolimus, mycophenolate mofetil)

               3. 3 month washout for leflunomide, IVIg or cyclophosphamide

               4. 6 month washout for rituximab

               5. 8 week washout for infliximab or adalimumab

               6. 2 week washout for etanercept

               7. 1 week washout for anakinra

          9. If an IS agent is continued, the dose must remain stable for 4 weeks prior to
             enrollment and at least until the DOI is met or if safety/toxicity issues supervene.
             Concomitant IS medications permitted include methotrexate, azathioprine, cyclosporine,
             mycophenolate mofetil, and tacrolimus. IVIg will also be allowed as an
             immunomodulatory agent. Careful patient safety monitoring along with American College
             of Rheumatology (ACR) guidelines for monitoring these medications will be employed if
             those toxicity monitoring laboratory studies are not already being assessed as part of
             this trial. No concomitant biologic agents are allowed (rituximab, anti-TNFs,
             abatacept) as well as cyclophosphamide or tofacitinib as concomitant immunosuppressive
             agents. Investigators will be certain to assess and classify adverse events as being
             secondary to either study drug as well as any concomitant immunosuppressive agent(s).
             That is, there should be attribution of the adverse event (AE) to the appropriate
             agent.

         10. Normal organ function, except if abnormal due to the disease under investigation

         11. Men and women of reproductive potential must agree to use an acceptable method of
             birth control during treatment and for twelve months after completion of treatment.

         12. Subject has provided written informed consent.

        Exclusion Criteria:

        A patient will be excluded if any of the following criteria are met:

          1. Subjects under the age of 18.

          2. Severe muscle damage defined as a global muscle damage score >5 on a 10cm VAS scale on
             the Muscle Damage Index (MDI).

          3. Evidence of active malignant disease, malignancies diagnosed within the previous 5
             years (including hematological malignancies and solid tumors, except basal and
             squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has
             been excised and cured), or breast cancer diagnosed within the previous 10 years
             unless related to primary disease under investigation.

          4. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial
             or other infections (including but not limited to tuberculosis and atypical
             mycobacterial disease, Hepatitis B and C, and herpes zoster, but excluding fungal
             infections of nail beds).

          5. Any major episode of infection requiring hospitalization or treatment with IV
             antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to
             screening.

          6. Active tuberculosis (TB) requiring treatment within the previous 3 years. Patients
             should be screened for latent TB and, if positive, treated following local practice
             guidelines prior to initiating TCZ. Patients treated for tuberculosis with no
             recurrence in 3 years are permitted.

          7. Primary or secondary immunodeficiency (history of or currently active) unless related
             to primary disease under investigation.

          8. Pregnant women or nursing (breast feeding) mothers.

          9. Patients with reproductive potential not willing to use an effective method of
             contraception.

         10. History of alcohol, drug or chemical abuse within 1 year prior to screening or any
             medical condition or physical or psychological state that the PI feels would not allow
             the subject to safely complete the study.

         11. Initiation of an exercise program for muscle strengthening within 4 weeks of the
             screening visit or initiation of a muscle strengthening exercise program during the
             study.

         12. Major surgery (including joint surgery) within 8 weeks prior to screening or planned
             major surgery within 6 months following randomization.

         13. Treatment with any investigational agent within 4 weeks (or 5 half-lives of the
             investigational drug, whichever is longer) of screening.

         14. Previous treatment with the following cell-depleting therapies, including
             investigational agents or approved therapies: CAMPATH, cluster of differentiation 4
             (anti-CD4), cluster of differentiation antigen 5 (anti-CD5), and anti¬CD3.

         15. Immunization with a live/attenuated vaccine within 4 weeks prior to baseline.

         16. Previous treatment with tocilizumab (TCZ).

         17. History of severe allergic or anaphylactic reactions to human, humanized or murine
             monoclonal antibodies.

         18. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary
             (including obstructive pulmonary disease), renal, hepatic, endocrine (include
             uncontrolled diabetes mellitus) or gastrointestinal disease (including complicated
             diverticulitis, ulcerative colitis, or Crohn's disease.)

         19. Patients with lack of peripheral venous access.

         20. Body weight of > 150 kg.

         21. Abnormal laboratory values noted below:

               1. Serum creatinine > 1.6 mg/dL in female patients and > 1.9 mg/dL in male patients.
                  Patients with serum creatinine values exceeding limits may be eligible for the
                  study if their estimated glomerular filtration rates (GFR) are >30.

               2. Platelet count < (100,000/mm3); hemoglobin < 8.5 g/dl and white blood cell count
                  (WBC) < 3000/mm3; Absolute Neutrophil Count < 2.0 x 109/L (2000/mm3); Absolute
                  Lymphocyte Count < 0.5 x 109/L (500/mm3)

         22. Positive hepatitis B surface antigen or hepatitis C antibody