Tocilizumab in the Treatment of Refractory Polymyositis and Dermatomyositis

Overview

About this study

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).

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Please contact the study team to discuss whether or not you are eligible to participate in a study.

Inclusion Criteria:

Patients will be included in the trial based on the following criteria:

  1. Definite or probable PM or 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 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-SRP, anti-Mi-2, anti-PM-Scl, 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, IVIg, anti-TNF agents, and rituximab).
  4. Subjects with an 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 VAS score on the 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. HAQ disability index with a minimum value of 0.25
    4. Elevation of at least one of the muscle enzymes (CK, AST, ALT, aldolase, LDH) at a minimum level of 1.3x the 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 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 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 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 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 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, anti-CD4, anti-CD5, and anti¬CD3.
  15. Immunization with a live/attenuated vaccine within 4 weeks prior to baseline.
  16. Previous treatment with 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 WBC count < 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 BsAg or hepatitis C antibody

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status

Rochester, Minn.

Mayo Clinic principal investigator

Floranne Ernste, M.D.

Closed for enrollment

More information

Publications

  • Since approval of tocilizumab (TCZ) for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), interleukin 6 (IL-6) pathway inhibition was evaluated in trials of TCZ and other agents targeting the IL-6 receptor and ligand in various RA populations and other inflammatory diseases. This consensus document informs on interference with the IL-6 pathway based on evidence and expert opinion. Read More on PubMed
  • Suppression of the immunoinflammatory cascade by targeting interleukin 6 (IL-6) mediated effects constitutes a therapeutic option for chronic inflammatory diseases. Tocilizumab is the only IL-6 inhibitor (IL-6i) licensed for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), but also other agents targeting either IL-6 or its receptor are investigated in various indications. Read More on PubMed
  • To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase trial in adult and pediatric myositis patients. Read More on PubMed
  • Circulating plasmablasts/plasma cells and activated B and T cells are increased in systemic lupus erythematosus (SLE). Interleukin (IL)-6 induces differentiation of B cells into antibody-forming cells and of T cells into effector cells. Read More on PubMed
  • The purpose of this study was to review the potential importance of interleukin 6 (IL-6) in systemic sclerosis (SSc). Read More on PubMed
  • In the past decade, tocilizumab, an anti interleukin-6 agent, has been successfully developed as a therapeutic agent for the treatment of rheumatoid arthritis and systemic onset juvenile idiopathic arthritis. In addition to countering inflammation, tocilizumab is also known affect B cell as well as T cell function, thus modulating immune function, and impact osteoclasts, as well as vascular endothelial growth factor. As such, its efficacy is currently being explored in a large number of autoiommune conditions including a number of vasculitides, systemic lupus erythematosus, systemic sclerosis, polymyositis, graft versus host disease, relapsing polychondritis, as well as Behcet's syndrome, spondyloarthropathies, and tumor necrosis factor receptor associated periodic syndrome. Read More on PubMed
  • Up-regulation of whole blood type I interferon (IFN)-driven transcripts and chemokines has been described in a number of autoimmune diseases. An IFN gene expression "signature" is a candidate biomarker in patients with dermatomyositis (DM). This study was performed to evaluate the capacity of IFN-dependent peripheral blood gene and chemokine signatures and levels of proinflammatory cytokines to serve as biomarkers for disease activity in adult and juvenile DM. Read More on PubMed
  • To explore new molecular targets in the treatment of polymyositis (PM) by examining a recently established murine model of PM, C protein-induced myositis (CIM), for involvement of an interleukin-6 (IL-6)/IL-17A pathway. Read More on PubMed
  • To establish a new murine model of polymyositis (PM) for the understanding of its pathologic mechanisms and the development of new treatment strategies. Read More on PubMed
  • Inflammatory/immune reactions against muscle cells are responsible for the damage in idiopathic inflammatory myopathies. We investigated the role of IL-6, a cytokine known to contribute to local leukocyte accumulation, in a model of myosin-induced experimental myositis. After injection of rabbit myosin in CFA/pertussis toxin, normal mice develop clinically evident muscle deficit and damage, as demonstrated by myofiber necrosis and leukocyte infiltration, while IL-6-deficient mice have no clinical or histological signs of muscle damage. This study evidences that selective deficiency of IL-6 directly or indirectly hinders the local inflammatory response and its harmful effects in this model of muscle damage. Read More on PubMed
  • There is no universal agreement on the definition of anaphylaxis or the criteria for diagnosis. In July 2005, the National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network convened a second meeting on anaphylaxis, which included representatives from 16 different organizations or government bodies, including representatives from North America, Europe, and Australia, to continue working toward a universally accepted definition of anaphylaxis, establish clinical criteria that would accurately identify cases of anaphylaxis with high precision, further review the evidence on the most appropriate management of anaphylaxis, and outline the research needs in this area. Read More on PubMed
  • To use a core set of outcome measures to develop preliminary definitions of improvement for adult and juvenile myositis as composite end points for therapeutic trials. Read More on PubMed

Study Results Summary

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Supplemental Study Information

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CLS-20150023

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