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About
Dermatomyositis (DM) is a rare and disabling condition with an important impairment of quality of life and possible life-threatening complications.
Treatment is based on high doses of corticosteroids but this exposes patients to adverse events (cardiovascular mortality, glucocorticoids-induced muscle and skin damages). Corticosteroids taper is associated with disease relapses. Although there is no evidence from the literature, clinical practice guidelines recommends the use of DMARDs such as methotrexate. However, response is not complete and these DMARDS take time to act.
The interferon type I (IFN-I) pathway is involved in the pathophysiology of DM. Janus kinase 1 and 2 transduces IFN-I signals. In addition, JAK2 inhibition enhances muscle repair and force generation.
JAK 1/2 inhibitors permitted to dramatically and rapidly improve relapsing DM patients (n=4, case series).
Our hypothesis is that Janus kinase 1 and 2 (JAK1/2) inhibitors (baricitinib) will permit to obtain dermatomyositis (DM) improvement with a steroid sparing effect as compared to usual care.
Our primary objective is to evaluate the efficacy of baricitinib (JAK1/2 inhibitor) to obtain prednisone-free moderate improvement (ACR/EULAR ≥ 40) of DM as compared to placebo in addition to usual care.
BIRD is a multicenter phase III double blind randomized placebo-controlled trial with two parallel arms (1:1). This is an add-on trial to usual care with rapid corticoid taper.
This is a multicenter trial in different medical departments in hospitals across France in different regions.
Out- and in patients will be recruited in hospital departments involved in management and diagnosis of DM: departments of dermatology, rheumatology and internal medicine.
Full description
Dermatomyositis (DM) is a rare and disabling condition with an important impairment of quality of life and possible life-threatening complications.
Treatment is based on high doses of corticosteroids but this exposes patients to adverse events (cardiovascular mortality, glucocorticoids-induced muscle and skin damages). Corticosteroids taper is associated with disease relapses. Although there is no evidence from the literature, clinical practice guidelines recommends the use of DMARDs such as methotrexate. However, response is not complete and these DMARDS take time to act.The interferon type I (IFN-I) pathway is involved in the pathophysiology of DM. Janus kinase 1 and 2 transduces IFN-I signals. In addition, JAK2 inhibition enhances muscle repair and force generation .
JAK 1/2 inhibitors permitted to dramatically and rapidly improve relapsing DM patients (n=4, case series) .
BIRD is a multicenter phase III double blind randomized placebo-controlled trial with two parallel arms (1:1). This is an add-on trial to usual care with rapid corticoid taper. Both groups (experimental and control groups) will receive corticosteroids and the conventional immunosuppressive drug (either azathioprine or methotrexate)
Our primary objective is to evaluate the efficacy of baricitinib (JAK1/2 inhibitor) to obtain prednisone-free DM moderate improvement as compared to placebo, in addition to usual care.
Primary endpoint: moderate improvement (defined as a total improvement score superior or equal to 40 following ACR/EULAR definition) without corticosteroids at week 24 (prednisone-free moderate improvement).
This multicenter trial involves different medical departments in hospitals across France in different regions. Out- and in patients will be recruited in hospital departments involved in management and diagnosis of DM: departments of dermatology, rheumatology and internal medicine.
Eligible patients will sign a written informed consent after full oral and written information about the trial. They will be randomized in 1:1 ratio to receive baricitinib plus prednisone taper plus one immunosuppressive drug (either methotrexate or azathioprine) (experimental group) or placebo plus prednisone taper plus one immunosuppressive drug (either methotrexate or azathioprine) (control group) for a duration of 24 weeks. In both groups, corticosteroids are tapered following a predefined protocol.
5 visits are planned:
The primary analysis will be the comparison between experimental and control groups of the rate of prednisone-free moderate improvement at 24 weeks in the intent to treat population. In order to demonstrate a difference in the rate of primary outcome at 24 weeks from 30% in the control group to 70% in the experimental group, with a power of 80%, a bilateral alpha risk of 5%, and a 15% rate of loss of follow-up, 62 patients are necessary.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Adult subjects (≥ 18 years old) < 65 years old
Dermatomyositis defined according to the 239th ENMC criteria either naïve or non-naïve DM
Active disease (ACR/EULAR criteria) defined as :
for relapsing/non naïve DM patients :
Affiliation to a social security regime
Written informed consent
Exclusion criteria
Life-threatening complications :
Patient with deep vein thrombosis/pulmonary embolism or antecedent
Patient with antecedent of cardiovascular event (myocardial infarction or ischemic stroke)
Patient who is current or past long-time smoker
Pregnant or lactating, or women planning to become pregnant or initiating breastfeeding
No effective contraception during the study and one week after for women of childbearing age
Renal impairment defined as clearance < 60 ml
Strong Organic Anion Transporter 3 (OAT3) inhibitors
Active cancer or history of malignancy
Active severe infection including active hepatitis
Evidence of latent tuberculosis (as documented by a positive QuantiFERON-TB Gold plus test)
Absolute Neutrophil Count < 1x109 cells/L
Haemoglobin (Hb) < 8 g/dL
Severe hepatic impairment attested by FV (coagulation factor)<30%
Liver insufficiency (Prothrombin time <60%)
Previous treatment exposure defined as follow : • Rituximab treatment within 6months before inclusion
Hypersensitivity to the active substance (baricitinib) or to any of the excipients
Contraindication to Methotrexate and/or Azathioprine including hypersensitivity to the active substances or to any of the excipients
Conditions affecting the outcomes (Expected poor compliance)
Severe disease damages: e.g. muscle weakness mainly related to muscle damage such as fat replacement of muscle) defined as persistent changes in anatomy, physiology, pathology or function which result from previously active disease and from complications of therapy or other events (e.g.; muscle atrophy, fatty replacement; skin scars, poikiloderma ). Severe disease damage is considered when the patient condition has no or minor ability to improve with the treatment.
Significant uncontrolled cardiovascular, cerebrovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic, or neuropsychiatric disorders, or abnormal laboratory values that developed during a qualifying study that, in the opinion of the investigator, poses an unacceptable risk for the patient's participation
Chest imaging (CT scan or radiograph) showing abnormalities not related with the DM in the last 12 weeks judged by the investigator as clinically significant.
Participants included in other intervention research involving humans
Patient under tutorship or guardianship, and incapable to give informed consent
Primary purpose
Allocation
Interventional model
Masking
62 participants in 2 patient groups, including a placebo group
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Central trial contact
YVES ALLENBACH, MD, PhD; SARRA POCHON
Data sourced from clinicaltrials.gov
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