Tocilizumab in the Treatment of Refractory Polymyositis and Dermatomyositis (TIM)
|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|
- 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).
- 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
- Hypersensitivity reactions and anaphylaxis
- Demyelinating disorders
- 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.
- 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 ]
|Study Start Date:||October 2014|
|Estimated Study Completion Date:||January 2017|
|Estimated Primary Completion Date:||August 2016 (Final data collection date for primary outcome measure)|
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).
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).
Other Name: Actemra
Placebo Comparator: Group B: Placebo
Placebo arm - no active drug
given by IV infusion every 4 weeks at 6 time points (Visits 1, 2, 3, 4, 5 and 6).
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02043548
|Contact: Chester V. Oddis, MDemail@example.com|
|Contact: Diane Koontzfirstname.lastname@example.org|
|United States, California|
|Cedars Sinai Medical Center||Recruiting|
|Losa Angeles, California, United States, 90048|
|Contact: Florence Figueras 310-360-9197 email@example.com|
|Principal Investigator: Swamy Venuturupalli, MD|
|Sub-Investigator: Lindsy J Forbess, MD, MSc|
|Sub-Investigator: Daniel J Wallace, MD, FACP|
|Sub-Investigator: Michael H Weisman, MD|
|United States, Kansas|
|University of Kansas Medical Center||Recruiting|
|Kansas City, Kansas, United States, 66160|
|Contact: Tina Liu 913-945-9932 firstname.lastname@example.org|
|Principal Investigator: Richard J. Barohn, MD|
|Principal Investigator: Mazen Dimachkie, MD|
|United States, Minnesota|
|Rochester, Minnesota, United States, 55905|
|Contact: Jenni Sletten 507-284-3695 email@example.com|
|Contact: Betty Dicke 507-266-4175 firstname.lastname@example.org|
|Principal Investigator: Floranne Ernste, MD|
|Sub-Investigator: Steven Ytterberg, MD|
|United States, New York|
|North Shore Long Island Jewish Center||Recruiting|
|Great Neck, New York, United States, 11021|
|Contact: Jessica Cristian 516-708-2546 email@example.com|
|Principal Investigator: Galina Marder, MD|
|United States, Pennsylvania|
|University of Pittsburgh||Recruiting|
|Pittsburgh, Pennsylvania, United States, 15261|
|Contact: Diane C. Koontz 412-383-8674 firstname.lastname@example.org|
|Principal Investigator: Chester V. Oddis, MD|
|Principal Investigator: Rohit Aggarwal, MD|
|Sub-Investigator: Siamak Moghadam-Kia, MD|
|United States, Tennessee|
|Nashville, Tennessee, United States, 37235|
|Contact: Meena Golchha 615-525-7667 email@example.com|
|Principal Investigator: Leslie Crofford, MD|
|United States, Wisconsin|
|Medical College of Wisconsin||Recruiting|
|Milwaukee, Wisconsin, United States, 53226|
|Contact: Marit Johnson 414-955-7022 firstname.lastname@example.org|
|Principal Investigator: David Gazeley, MD|
|Principal Investigator:||Chester V. Oddis, MD||University of Pittsburgh|