Tocilizumab in the Treatment of Refractory Polymyositis and Dermatomyositis (TIM)
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|ClinicalTrials.gov Identifier: NCT02043548|
Recruitment Status : Completed
First Posted : January 23, 2014
Results First Posted : October 30, 2020
Last Update Posted : October 30, 2020
|Condition or disease||Intervention/treatment||Phase|
|Dermatomyositis Polymyositis||Drug: tocilizumab Drug: placebo||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||36 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Official Title:||Tocilizumab in the Treatment of Refractory Polymyositis and Dermatomyositis|
|Actual Study Start Date :||October 1, 2014|
|Actual Primary Completion Date :||July 30, 2019|
|Actual Study Completion Date :||July 31, 2019|
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).
- Compare the Average Total Improvement Scores at Visits 2 Through 7 During the 6-month Treatment Period Between the Treatment and Placebo Arms [ Time Frame: Week 4, 8, 12, 16, 20, and 24 ]
The total improvement score was calculated by adding the improvement scores of all six core set measures based on 2016 American College of Rheumatology (ACR)/European League Against Rheumatism(EULAR) myositis response criteria.
The minimum and maximum values of the average Total Improvement Scores are 0 and 100; The minimum and maximum values of the average Total Improvement Scores of our included patients are 5.0 and 67.1; The higher scores mean a better outcome.
- Comparison of the Time to First Definition of Improvement (DOI) Between the 2 Arms [ Time Frame: Week 4, 8, 12, 16, 20, and 24 ]Time to achieve the first DOI between the treatment and placebo arms.The total improvement score (TIS) is the sum of all 6 improvement scores associated with the change in each core set measure. A TIS >= 20 represents minimal improvement, a score of >=40 represents moderate improvement, and a score of >=60 represents major improvement.
- Count of the Adverse Events Between the Treatment and Placebo Arms. [ Time Frame: Week 4, 8, 12, 16, 20, and 24 ]We compared the count of the adverse events between the treatment and placebo arms statistically.
- Comparison of the Steroid-sparing Effect (Calculated Using Prednisone Dose Equivalents) Between the Treatment and Placebo Arms [ Time Frame: Week 4, 8, 12, 16, 20, and 24 ]Mean change of steroid dose prednisone equivalent from last visit to baseline visit was compared between the two treatment arms
- Comparison of Individual Average Core Set Measure in Subjects Over Time Between the 2 Arms (Repeated Measures Analysis) [ Time Frame: Week 4, 8, 12, 16, 20, and 24 ]
The core set measure tested was manual muscle testing, and we compared the mean manual muscle test measures in subjects over time.
The minimum and maximum values of the manual muscle testing are 0 and 150; The minimum and maximum values of the manual muscle testing of our included patients are 97.0 and 150.0; The higher scores mean a better outcome.
- Magnitude of the Effect Size Between the Both Treatment Arms [ Time Frame: Week 4, 8, 12, 16, 20, and 24 ]Compared the number of subjects meeting total improvement scores >=20 (minimal) and >=40 (moderate) and >=60 (major) based on 2016 ACR EULAR myositis response criteria for treatment group and placebo group. The highest TIS score achieved from week 4 through week 24 was used to determine the effect size between both treatment arms.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02043548
|United States, California|
|Cedars Sinai Medical Center|
|Los Angeles, California, United States, 90048|
|United States, Kansas|
|University of Kansas Medical Center|
|Kansas City, Kansas, United States, 66160|
|United States, Minnesota|
|Rochester, Minnesota, United States, 55905|
|United States, New York|
|North Shore Long Island Jewish Center|
|Great Neck, New York, United States, 11021|
|United States, Pennsylvania|
|University of Pittsburgh|
|Pittsburgh, Pennsylvania, United States, 15261|
|United States, Tennessee|
|Nashville, Tennessee, United States, 37235|
|United States, Wisconsin|
|Medical College of Wisconsin|
|Milwaukee, Wisconsin, United States, 53226|
|Principal Investigator:||Chester V. Oddis, MD||University of Pittsburgh|