Effect of Tofacitinib in Treating ANCA-associated Vasculitis

Study Overview
=================
Brief Summary
-----------------
The goal of this study is to evaluate the efficacy and safety of tofacitinib 5 mg twice daily in AAV patients.

Detailed Description
-----------------
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) represents a group of small vessel vasculitides characterized by granulomatous and neutrophilic tissue inflammation, often associated with the production of antibodies that target neutrophil antigens. The predominantly used treatment for induction of remission in AAV consisted of cyclophosphamide (CYC) plus corticosteroids (GCs) which leads to remission in about 90% of patients. However, relapses are frequent and remain a challenge. The optimal drug for maintenance treatment is not determined. Tofacitinib is a Jak inhibitor which has been proved to be effective in multiple inflammatory diseases such as rheumatoid arthritis. Considering that T cells and associated cytokine production play an important role in the pathogenesis of AAV via activation of the JAK/ STAT pathway, we hypothesized that tofacitinib-mediated inhibition of JAK signaling may represent an effective therapy for active AAV. In this prospective, open label, single arm study, tofacitinib 5mg twice a day will be added to the background treatment of GCs and immunosuppressants in AAV, the safety and efficacy of tofacitinib will be assessed.

Official Title
-----------------
Tofacitinib for the Treatment of Anti-Neutrophil Cytoplasm Antibody-associated Vasculitis: a Pilot Study

Conditions
-----------------
ANCA Associated Vasculitis, Drug Use, JAK-STAT Pathway Deregulation

Intervention / Treatment
-----------------
* Drug: Tofacitinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with active AAV met the criteria of 1990 ACR and 2012 Chapel Hill criteria Age 18 to 75 years Written informed consent obtained before taking part in the study Exclusion Criteria: Severe AAV defined as potentially organ- or life-threatening disease (i.e. alveolar haemorrhage, heart failure caused by myocarditis or pericarditis, progressive neurological symptoms, deaf, blindness, et al.) Serum creatinine>120umol/L or proteinuria>1.0g/d Receipt of a JAKi therapy previously Co-existence of another systemic autoimmune disease Secondary vasculitis (following neoplastic disease, an infection or antithyroid drugs) Malignancy or history of malignancy Infection by HIV, HCV, HBV or tuberculosis- Severe uncontrolled cardiovascular, pulmonary, liver, gastrointestinal, endocrine, hematological, neurological, or psychiatric diseases that are not related to systemic vasculitis Allergic to JAKi Blood dyscrasias including confirmed: Hemoglobin <9 g/dL or Hematocrit <30%; White blood cell count <3.0 x 109/L; Absolute neutrophil count <1.5 x 109/L; Platelet count <100 x 109/L; Alanine transaminase or aspartate aminotransferase or total bilirubin>1.5 upper normal limit; Estimated glomerular filtration rate<60ml/min/1.73m2 Incapacity or refusal to understand or sign the informed consent form. Pregnancy, breastfeeding.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tofactitinib<br>Tofacitinib 5mg twice a day | Drug: Tofacitinib<br>* patients enrolled were prescribed tofacitinib 5mg twice a day orally.<br>* Other names: Tofacitinib 5mg.bid.po.;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The response rate (CR, PR and TR) | The percent of patients who achieved disease response. The disease response includes:(1) complete remission (CR), defined as the absence of disease activity (BVAS = 0); (2) partial remission (PR) defined as at least 50% reduction of BVAS and no new manifestations; (3) treatment resistance (TR) was defined as less than a 50% reduction or increased disease activity after 4   6 weeks of treatment. | From the enrollment to the end of follow-up [0 to 13 months.] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of adverse event | The percent of different kinds of adverse events occurred during follow-up. The adverse event was evaluated according to the CTC-AE 4.0 standard. | From the enrollment to the end of follow-up [0 to 13 months]. | 
| Changes in erythrocyte sedimentation rate (ESR) | The change of ESR in different follow-up point compared with the baseline. | From the enrollment to the end of follow-up [0 to 13 months]. | 
| Changes in CRP | The change of CRP in different follow-up point compared with the baseline. | From the enrollment to the end of follow-up [0 to 13 months]. | 
| Changes in glucocorticoids steroids (GCs) dosage | The change of the prednisone or its equivalent drug in different follow-up point compared with the baseline. | From the enrollment to the end of follow-up [0 to 13 months]. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ANCA associated vasculitis, tofacitinib, safety, efficacy