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The Efficacy and Safety of JAK Inhibitor in the Treatment of Anti-MDA5 Antibody-positive Dermatomyositis Patients

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ClinicalTrials.gov Identifier: NCT04966884
Recruitment Status : Recruiting
First Posted : July 19, 2021
Last Update Posted : July 19, 2021
Sponsor:
Information provided by (Responsible Party):
First Affiliated Hospital Xi'an Jiaotong University

Study Description
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Brief Summary:
Anti-melanoma differentiation-associated gene5 (Anti-MDA5) antibody positive Dermatomyositis (DM) is a subtype of DM that is more frequent in East Asia, which is often exhibit skin lesion, clinically amyopathic and interstitial lung disease. About 42%-100% of patients with Anti-MDA5+ DM develop rapidly progressive interstitial lung disease (RPILD) and result in respiratory failure. The mortality is as high as 40% within 6 months. In addition, not every patient with Anti-MDA5+ DM respond to traditional treatment strategy and most of the patients are resistant to immunosuppressive therapy including a combination of high dose glucocorticoids (GCs) and immunosuppressants such as cyclosporine, tacrolimus, or cyclophosphamide. However, RP-ILD is still the main cause of death due to fatal respiratory failure. Therefore, treatment of Anti-MDA5+ DM patients is challenging.Blocking multiple cytokines may become a new target for the treatment of this disease.Jakinibs is a Janus kinase (JAK) inhibitor that blocks a variety of cytokines, such as type I and type II interferon. Few studies have reported a positive response to JAK inhibitor for Anti-MDA5+ DM. Kazuhiro et al. reported in 2018 that JAK inhibitor tofacitinib may be an effective treatment option for high risk amyopathic dermatomyositis (ADM) -ILD patients after failure of conventional treatment, but the number of cases is too small. And a recent paper showed that great efficacy of tofacitinib for the improvement of survival of anti-MDA5-positive early-stage ADM-ILD patients.The aim of this study is to evaluate the efficacy and safety of JAK inhibitors in the treatment of anti-MDA5+ DM patients, and to evaluate the effect of JAK inhibitors on B cells of these patients, so as to provide a new target and theoretical basis for the treatment of anti-MDA5+ DM.

Condition or disease Intervention/treatment Phase
Dermatomyositis, Adult Type Drug: JAK Inhibitor Phase 4

Detailed Description:
Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by chronic inflammation in the skin and muscle. Anti-melanoma differentiation-associated gene5 (Anti-MDA5) antibody positive DM is a subtype of DM that is more frequent in East Asia, which is often exhibit skin lesion, clinically amyopathic and interstitial lung disease. About 42%-100% of patients with Anti-MDA5+ DM develop rapidly progressive interstitial lung disease (RPILD) and result in respiratory failure. The mortality is as high as 40% within 6 months. In addition, not every patient with Anti-MDA5+ DM respond to traditional treatment strategy and most of the patients are resistant to immunosuppressive therapy including a combination of high dose glucocorticoids(GCs) and immunosuppressants such as cyclosporine, tacrolimus, or cyclophosphamide. However, RP-ILD is still the main cause of death due to fatal respiratory failure. Therefore, treatment of Anti-MDA5+ DM patients is challenging.The excessive production of multiple cytokines plays a crucial role in the development of Anti-MDA5+ DM patients complicated with ILD. Hyperferritinemia is a predictor of poor prognosis. Other abnormalities included lymphopenia, increased erythrocyte sedimentation rate(ESR), and elevated serum interleukin-18 (IL-18).Moreover, compared with Anti-MDA5- DM patients, serum interferon--α(IFN-α) concentration increased in Anti-MDA5+ DM patients with RP-ILD. Therefore, blocking multiple cytokines may become a new target for the treatment of this disease.Jakinibs is a Janus kinase (JAK) inhibitor that blocks a variety of cytokines, such as type I and type II IFN. Few studies have reported a positive response to JAK inhibitor for Anti-MDA5+ DM. Kazuhiro et al. reported in 2018 that JAK inhibitor tofacitinib may be an effective treatment option for high risk amyopathic dermatomyositis (ADM) -ILD patients after failure of conventional treatment, but the number of cases is too small. And a recent paper showed that great efficacy of tofacitinib for the improvement of survival of anti-MDA5-positive early-stage ADM-ILD patients.The aim of this study is to evaluate the efficacy and safety of JAK inhibitors in the treatment of anti-MDA5+ DM patients, and to evaluate the effect of JAK inhibitors on B cells of these patients, so as to provide a new target and theoretical basis for the treatment of anti-MDA5+ DM.This was a single-arm open-label pilot observational study. Patients were received a glucocorticoids (0.8mg-1mg/kg/day) and a combination with tofacitinib (at a dose of 5 mg twice daily). Inactive disease was defined as meeting the following three criteria: CK≤200U/L, physician visual analogue scale(VAS) =0, and myositis disease activity assessment visual analog scales (MYOACT) scores =0. Otherwise, the disease condition was considered to be active.The primary endpoint was the number of responders by total improvement score (TIS) ,which defined according to 2016 American College of Rheumatology(ACR)-European League Against Rheumatism(EULAR) Criteria for clinical response for adult DM/polymyositis(PM), after treatment with tofacitinib for 12 months. A TIS (0-100), determined by summing scores in each International Myositis Assessment and Clinical Studies Group (IMACS) core set measures (CSM). Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the TIS. Secondary endpoints included safety measures and change from baseline in the following index: percentage of predicted FVC (FVC % predicted) and percentage of predicted DLCO (DLCO% predicted), the ferritin level, peripheral lymphocyte subsets.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Efficacy and Safety of JAK Inhibitor in the Treatment of Anti-MDA5 Antibody-positive Dermatomyositis Patients
Actual Study Start Date : April 2, 2020
Estimated Primary Completion Date : December 30, 2021
Estimated Study Completion Date : December 30, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: A single-arm open-label pilot observational study
Patients were received a glucocorticoids (0.8mg-1mg/kg/day) and a combination with tofacitinib (at a dose of 5 mg twice daily).
 Drug: JAK Inhibitor
  1. Prednisone 0.8-1.0 mg/kg/d, the dose was gradually reduced, and after 4 weeks, the dose was reduced by 5mg every two weeks, and then reduced to 10mg/d for 4-6 months after oral administration for 3 months, and then reduced to 7.5mg/d for maintenance therapy until 12 months;
  2. Tofacitinib 5 mg twice daily for 12 months.


Outcome Measures
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Primary Outcome Measures :
  1. TIS [ Time Frame: 12 months ]
    the number of responders by total improvement score


Secondary Outcome Measures :
  1. FVC % predicted [ Time Frame: 12 months ]
    percentage of predicted FVC

  2. DLCO % predicted [ Time Frame: 12 months ]
    percentage of predicted DLCO

  3. Lung high resolution CT score [ Time Frame: 12 months ]
    Lung high resolution CT score

  4. Overall survival rate [ Time Frame: 12 months ]
    Overall survival rate%

  5. Infection rate [ Time Frame: 12 months ]
    Infection rate%


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • patients fulfilled the Bohan and Peter criteria;
  • anti-MDA5 antibody positive;
  • patients who were not receiving treatment, or previously diagnosed with anti- MDA5-positive DM, who did not use biological agents (including but not limited to rituximab, infliximab, adalimumab, etanercept, tofacitinib, etc.) at the time of screening, or who had stopped taking drugs for ≥3 months;

Exclusion Criteria:

  • patients if they had other connective tissue diseases, an underlying cancer, a concomitant infection, or a liver aminotransferase level greater than 2 times the upper limit of the normal range.
Contacts and Locations
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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): NCT04966884


Contacts
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Contact: Lan He 086-13809156236 Xajdhl87@mail.xjtu.edu.cn
Contact: Yanhua Wang 086-13571490573 1367677985@qq.com

Locations
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China, Shaanxi
Department of Rheumatology, the First Affiliated Hospital of Xi'an Jiaotong University Recruiting
Xi'an, Shaanxi, China, 710061
Contact: Yanhua Wang    13571490573 ext 086-    13571490573@163.com   
Contact: Lan He    13809156236    Xajdhl87@mail.xjtu.edu.cn   
Sponsors and Collaborators
First Affiliated Hospital Xi'an Jiaotong University
Investigators
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Study Chair: Lan He First Affiliated Hospital Xi'an Jiaotong University
More Information
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Publications of Results:

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Responsible Party: First Affiliated Hospital Xi'an Jiaotong University
ClinicalTrials.gov Identifier: NCT04966884    
Other Study ID Numbers: XJTU1AF2020LSK-193
First Posted: July 19, 2021    Key Record Dates
Last Update Posted: July 19, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by First Affiliated Hospital Xi'an Jiaotong University:
Dermatomyositis,Tofacitinib,anti-MDA5 antibody
Additional relevant MeSH terms:
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Dermatomyositis
Polymyositis
Myositis
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
 Connective Tissue Diseases
Skin Diseases
Janus Kinase Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action