Tocilizumab in the Treatment of Refractory Polymyositis and Dermatomyositis (TIM)

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified January 2014 by University of Pittsburgh
Sponsor:
Collaborator:
Genentech
Information provided by (Responsible Party):
Chester Oddis, University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT02043548
First received: January 17, 2014
Last updated: January 21, 2014
Last verified: January 2014
  Purpose

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).


Condition Intervention Phase
Dermatomyositis
Polymyositis
Drug: tocilizumab
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Tocilizumab in the Treatment of Refractory Polymyositis and Dermatomyositis

Resource links provided by NLM:


Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:
  • Proportion of subjects meeting the definition of improvement (DOI) [ Time Frame: Week 4 through week 24 ] [ Designated as safety issue: No ]
    The primary outcome will be to compare the proportion of subjects meeting the definition of improvement (DOI) at visits 2 through 7 during the 6-month treatment period between the treatment and placebo arms. The DOI for this trial is a composite utilizing the six CSM: 3 of 6 CSM improved by ≥ 20%, with no more than 2 CSM worsening by ≥25% (a worsening measure cannot be the MMT).


Secondary Outcome Measures:
  • Comparison of the time to first DOI between the 2 arms [ Time Frame: Week 4 through week 24 ] [ Designated as safety issue: No ]
    Comparing the proportion of subjects meeting DOI in the treatment and placebo arms on 2 consecutive visits, and determination of the time to flare [meeting the definition of worsening (DOW)] in those who earlier met the DOI.

  • frequency of defined adverse events between the treatment and placebo arms. [ Time Frame: Week 0 through week 36 ] [ Designated as safety issue: Yes ]

    We will statistically compare the frequency of the following adverse events between the treatment and placebo arms:

    • Infections including all opportunistic infections and non-serious infections as defined by those treated with IV anti-infectives
    • Myocardial infarction/acute coronary syndrome
    • GI perforation and related events
    • Malignancies
    • Hypersensitivity reactions and anaphylaxis
    • Demyelinating disorders
    • Stroke
    • Bleeding events
    • Hepatic events

    Similarly, we will analyze the proportion of serious adverse events between the treatment and placebo arms. In addition, the number and percent of patients with AEs during the treatment period will be summarized.



Other Outcome Measures:
  • comparison of the change in the individual core set measures in subjects over time between the 2 arms (repeated measures analysis) [ Time Frame: Week 4 through week 24 ] [ Designated as safety issue: No ]
  • Comparison of the steroid-sparing effect (calculated using prednisone dose equivalents) between the treatment and placebo arms [ Time Frame: Week 4 though week 36 ] [ Designated as safety issue: No ]
  • Assessment of the magnitude of the effect size between both treatment arms by comparing the proportion of subjects meeting a more stringent DOI (i.e. 30% and 40% improvement in CSM) as opposed to the published 20% improvement in DOI [ Time Frame: Week 4 through week 24 ] [ Designated as safety issue: No ]
  • The difference in adverse events between the control and treatment arms. [ Time Frame: Week 0 through week 36 ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 40
Study Start Date: April 2014
Estimated Study Completion Date: January 2017
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Group A: Tocilizumab
Tocilizumab will be 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).
Drug: tocilizumab
Other Name: Actemra
Placebo Comparator: Group B: Placebo
Placebo arm - no active drug
Drug: Placebo

Detailed Description:

Although there are several studies supporting the efficacy of tocilizumab (TCZ) in Rheumatoid Arthritis (RA) and systemic onset juvenile idiopathic arthritis, it's use in other autoimmune disorders has also been propose. A consensus statement on blocking the effects of IL-6 in RA and other autoimmune conditions has been recently published. IL-6 is involved in the growth and differentiation of many inflammatory cells. In addition to its initial role in triggering B-cell stimulating factor, it also induces T cell growth and differentiation and plays a critical role in both adaptive and innate immune responses. IL-6, produced by many cells including T cells, B cells, monocytes and endothelial cells, binds to its receptor (IL-6R) and subsequently triggers several intracellular pathways leading to the release of inflammatory mediators and stimulation of the immune system. Inhibition of IL-6 has been studied in phase II and III clinical trials of RA. It has led to a decrease in acute phase reactants and other indicators of chronic inflammation. IL-6 is also a potential therapeutic target in systemic sclerosis, and since IL-6 induces differentiation of B cells into antibody forming cells and contributes to T cells transforming into effector cells, its use in Systemic Lupus erythematosus (SLE) has also been suggested.

The use of TCZ in myositis proposed in this protocol is supported by the aforementioned rationale and its efficacy in other rheumatologic disorders. Patients with refractory polymyositis (PM) were treated with tocilizumab and responded favorably. In dermatomyositis, tissue inflammation implicates soluble cytokine networks contributing to disease pathogenesis. Work on a mouse model of myositis noted IL-6 as a mediator of muscle inflammation. Other investigators studying peripheral blood samples and clinical data on both adult and juvenile dermatomyositis (DM) noted that serum levels of IL-6 were significantly correlated with disease activity. In this same study, correlations between serum IL-6 levels and both the type I interferon gene and chemokine signatures were also identified in DM. These authors suggest that the coordinated dysregulation of IL-6 production and Type I interferon signaling implicates these pathways as contributing to disease pathogenesis in DM.

In a mouse model of PM, C protein-induced myositis (CIM), the pathology reportedly mimics that seen in human PM. Mice were treated with anti-IL-6 receptor monoclonal antibodies or control antibodies and muscle tissue was histologically and immunohistochemically analyzed. CIM was ameliorated in this mouse model implicating IL-6 in the development of myositis. These results not only identified this model as useful to understanding PM but they suggest that IL-6 blockade be considered as a new therapeutic approach in the treatment of myositis.

Thus, the collective findings described above provide evidence for the involvement of IL-6 in the pathogenesis of both adult PM and DM as well as supporting its role from animal models and human studies.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02043548

Contacts
Contact: Chester V. Oddis, MD 412-383-8861 cvo5@pitt.edu
Contact: Christine L. Amity, BS, RN 412-647-2638 amitycl@upmc.edu

Locations
United States, California
Cedars Sinai Medical Center Not yet recruiting
Losa Angeles, California, United States, 90048
Principal Investigator: Swamy Venuturupalli, MD         
United States, Kansas
University of Kansas Medical Center Not yet recruiting
Kansas City, Kansas, United States, 66160
Contact: Laura Herbelin, BS    913-588-5095    lherbelin@kumc.edu   
Principal Investigator: Richard J. Barohn, MD         
United States, Minnesota
Mayo Clinic Not yet recruiting
Rochester, Minnesota, United States, 55905
Contact: Jane Jaquith    507-284-4502    Jaquith.jane@mayo.edu   
Principal Investigator: Floranne Ernste, MD         
United States, New York
North Shore Long Island Jewish Center Not yet recruiting
Great Neck, New York, United States, 11021
Principal Investigator: Galina Marder, MD         
United States, Pennsylvania
University of Pittsburgh Not yet recruiting
Pittsburgh, Pennsylvania, United States, 15261
Contact: Christine L. Amity, BS, RN    412-647-2638    amitycl@upmc.edu   
Contact: Diane C. Koontz    412-383-8674    dik4@pitt.edu   
Principal Investigator: Chester V. Oddis, MD         
United States, Tennessee
Vanderbilt University Not yet recruiting
Nashville, Tennessee, United States, 37235
Principal Investigator: Leslie Crofford, MD         
United States, Wisconsin
Medical College of Wisconsin Not yet recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Marit Johnson    414-955-7022    mjohnson@mcw.edu   
Principal Investigator: Mary Cronin, MD         
Sponsors and Collaborators
University of Pittsburgh
Genentech
Investigators
Principal Investigator: Chester V. Oddis, MD University of Pittsburgh
  More Information

Publications:

Responsible Party: Chester Oddis, Chester Oddis, MD, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT02043548     History of Changes
Other Study ID Numbers: 0039599
Study First Received: January 17, 2014
Last Updated: January 21, 2014
Health Authority: United States: Institutional Review Board
United States: Data and Safety Monitoring Board

Keywords provided by University of Pittsburgh:
dermatomyositis
polymyositis
tocilizumab
Actemra

Additional relevant MeSH terms:
Dermatomyositis
Polymyositis
Myositis
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Connective Tissue Diseases
Skin Diseases

ClinicalTrials.gov processed this record on September 30, 2014