Takayasu Arteritis Clinical Trial in China

Study Overview
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Brief Summary
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The purpose of this study is to investigate the efficacy and Safety of Leflunomide in Patients With Active Phase of Takayasu's Arteritis

Official Title
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Comparison of the Efficacy and Safety of Leflunomide Versus Placebo Combine With the Basic Prednisone Therapy in Patients With Active Phase of Takayasu's Arteritis: a Randomized Controlled Double-blinded Trial

Conditions
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Takayasu Arteritis

Intervention / Treatment
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* Drug: Leflunomide 10mg Tab
* Drug: Prednisone Acetate
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form; Subjects who met the American College of Rheumatology 1990 classification criteria for Takayasu arteritis: 2.1 Age of onset ≤40 years; 2.2 Claudication of upper or lower extremities; 2.3 Decreased pulsation of 1 or both brachial arteries; 2.4 Difference of ≥ 10 mmHg in systolic blood pressure between arms; 2.5 Bruit over subclavian arteries or aorta; 2.6 Angiography * showing a branch of the aorta stenosis or occlusion; Meeting more than 3 of 6 criteria suggests the diagnosis of Takayasu arteritis. * Angiography in this study was replaced by vascular magnetic resonance angiography（MRA）or computed tomography angiography（CTA）. Males or females between the ages of 18 and 65 years; All subjects agreed to have no childbearing plan during the clinical trial, and the results of serum or urine pregnancy test for females must be negative; Evidence of disease in active phase during the past 3 months, meeting at least 2 of the following criteria: 5.1 There is a new onset of vascular ischemia ,in accordance with at least one of the following: 5.1.1 newly discovered difference of blood pressure between arms (systolic pulse pressure difference of at least ≥ 10mmHg); 5.1.2 new onset of decreased pulsation of 1 or both brachial arteries; 5.1.3 other new manifestations of vascular ischemia; 5.2 Inflammatory abnormalities, meeting at least one of the following: 5.2.1 Erythrocyte sedimentation rate（ESR） level higher than the normal upper limit（others factors like infection are excluded）; 5.2.2 high-sensitivity C-reactive protein（hsCRP）≥ 6mg/L or C-reactive protein（CRP）> 10mg/L; 5.3 Imaging examinations show abnormalities suggesting that disease is in active phase, meeting at least one of the following: 5.3.1 Vascular wall show enhanced signal on MRA(active inflammation); 5.3.2 enhanced CTA suggests new vascular lesions; 5.3.3 Color Doppler ultrasonography suggests vascular wall inflammation; 5.3.4 PET/CT suggests elevated SUV value on vascular wall; 5.4 Systemic symptoms that can not be explained by other causes: fever, fatigue or losing weight. If the patient is taking prednisone or its equivalent before screening, the dose should not exceed 0.6mg/kg/d and keep stable for at least 4 weeks before the first dose of the trial treatment; If the patient has previously received medication for Takayasu Arteritis, the withdrawal time before first dose of the trial treatment should meet: 7.1 Leflunomide: ≥ 6 months. If cholestyramine is used at least for 11 days, the withdrawal time required ≥ 4 weeks; 7.2 Cyclophosphamide ≥ 8 weeks; 7.3 Azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, tacrolimus, thalidomide, antimalarial or any other medication for Takayasu arteritis but not specifically allowed during the trial was not taken when the first dose of trial drugs were given; 7.4 Biological agents such as rituximab, IL-6 receptor antagonists, tumor necrosis factor inhibitors, etc.: ≥ 3 months; Exclusion Criteria: Takayasu arteritis which only show lesions of vascular dilatation or aneurysm formation; Takayasu arteritis patients who have received surgery related to revascularization for Takayasu arteritis (except percutaneoustransluminalangioplasty) within 3 months; or received percutaneoustransluminalangioplasty within 1 months; Subjects with organ failure, meeting at least one of the following: 3.1 Cardiac function: New York Heart Association grade 4; 3.2 Glomerular filtration rate ≤ 60ml/min; 3.3 Liver function： Child-pugh grade 2 and worse than grade 2; 3.4 High frequency of amaurosis (flare on 3 consecutive days); 3.5 Acute cerebral infarction or cerebral hemorrhage; 3.6 Blood pressure> 160/100mmHg; Suffer from other autoimmune diseases (eg, ANCA-associated vasculitis, systemic lupus erythematosus, Behcet's disease, etc.) besides Takayasu arteritis; Serious or progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, pulmonary, cardiac, neurological, or other coexisting medical conditions that are not associated with Takayasu's arteries but may result in unacceptable risks; Co-morbidities as asthma that may require the use of medium to high doses of glucocorticoids (prednisone ≥ 10 mg/day or equivalent doses of prednisone equivalents) during the study period; subjects with history of malignancy diseases; Subjects with any serious acute or chronic infection; Hepatitis B surface antigen positive or hepatitis B DNA positive; Hepatitis C antibody positive; Subjects with clinical or radiological or laboratory evidence of active tuberculosis; Subjects with abnormal laboratory test results, meeting at least 1 of the following: 12.1 Subjects with serum alanine aminotransferase (ALT) or glutamic-oxalacetic transaminase（AST）≥1.5 fold of the normal upper limit; 12.2 Blood white blood cell count ≤4×10^9 / L; 12.3 Platelet count ≤100 × 10^9 / L; 12.4 Hemoglobin ≤85g / L; 12.5 Other laboratory test abnormalities that may contribute to unacceptable risks for participants in this study; Subjects who are allergic to any of the investigational drugs; Use treatments and/or medication that are not allowed in this trial: 14.1 History of leflunomide treatment for at least 3 months but not effective; 14.2 Subjects who had undergone plasmapheresis or lymphocyte replacement or immunosorbent therapy in the last one year, or those who had planned to receive such treatments; 14.3 Patients who are willing to receive attenuated vaccine during the trial; 14.4 Subjects accepted or planned to have organ transplantation;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Leflunomide group<br>Use Leflunomide 20mg qd po. for 24 weeks for induced remission therapy combine with the basic prednisone therapy(start with 0.6mg/kg/d and maintained for 4 weeks, then reducing 5mg every 2 weeks until 10mg per day if the subject achieve clinical remission. If the subject has not achieve clinical remission,do not change prednisone dose）. Subjects who have achieved clinical remission, with the prednisone dose reduced to 10mg within 20 weeks and maintained to the end of 24 weeks enter the maintenance therapy.The next 32 weeks for maintenance therapy use leflunomide combine with prednisone 10mg per day. | Drug: Leflunomide 10mg Tab<br>* 20mg per day for leflunomide group during the entire study; 20mg per day for control group during the maintenance therapy (start from the 25th week till the end of the study).<br>Drug: Prednisone Acetate<br>* basic therapy（start with 0.6mg/kg/d and maintained for 4 weeks, then reducing 5mg every 2 weeks until 10mg per day if the subject achieve clinical remission.）<br>|
| Placebo Comparator: Control Group<br>Use Placebo for 24 weeks for induced remission therapy(24 weeks) and use leflunomide 20mg qd po. for maintenance therapy in the next 32 weeks. Prednisone is used as basic therapy during the whole trial (start with 0.6mg/kg/d and maintained for 4 weeks, then reducing 5mg every 2 weeks until 10mg per day if the subject achieve clinical remission. Then maintain 10mg per day until the end of the study). All subjects in control group enter maintenance therapy. | Drug: Leflunomide 10mg Tab<br>* 20mg per day for leflunomide group during the entire study; 20mg per day for control group during the maintenance therapy (start from the 25th week till the end of the study).<br>Drug: Prednisone Acetate<br>* basic therapy（start with 0.6mg/kg/d and maintained for 4 weeks, then reducing 5mg every 2 weeks until 10mg per day if the subject achieve clinical remission.）<br>Drug: Placebos<br>* used in control group during the induced remission therapy for 24 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants achieving clinical remission | Clinical remission is defined as follows: No systemic symptoms such as fever, fatigue and weight loss; without new onset of ischemic symptoms and ischemic signs; Serum Erythrocyte sedimentation rate(ESR）levels in normal range (if not, retest after 1 week, take the lower one into analyse); Subject achieving clinical remission should meet all these criteria above. | From the date of randomization until the end of induced remission therapy, assessed up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to achieve clinical remission |  | From the date of randomization until the date of first documented clinical remission, assessed up to 24 weeks | 
| Mean dose of prednisone in each group at the end of induced remission therapy |  | At the end of induced remission therapy, assessed up to 24 weeks | 
| Recurrence rate during leflunomide maintenance therapy | Recurrence is determined as follows:Kerr score>= 2 or do not meet two or more than two criteria of the clinical remission standard,and the results need to be reconfirm 28 days later. Kerr score: 1) presence of systemic symptoms as fever, fatigue and weight loss (1'); 2）presence of ischemic symptoms or signs (1'); 3) abnormal serum ESR levels (1'); 4) progression or new site of vascular lesions on MRA or CTA compared to baseline(1'). | From the beginning of maintenance therapy to the end of follow up, assessed up to 32 weeks(from the end of the 24th week till the end of the 56th week) | 
| Time to recurrence during leflunomide maintenance therapy |  | From the beginning of maintenance therapy (the 25th week) to the date of first documented recurrence, assessed up to 32 weeks | 
| Number of participants with adverse events related to leflunomide treatments | Adverse events include neutropenia, elevated serum level of liver enzymes(> 2 fold of normal upper limit), reproductive toxicity and infection | From the date of randomization until the end of this trial, assessed up to 56 weeks | 
| The changes of Doctor General Visual Analogue Scale at the end of 24 weeks and 56 weeks compared to baseline |  | From the date of randomization until the end of induced remission therapy (24 weeks) and maintenance therapy (56 weeks) | 
| The changes of participant self-reports at the end of 24 weeks and 56 weeks compared to baseline | Participant self-reports include Patients General Visual Analogue Scale, SF-36 quality of life questionnaire, and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale | From the date of randomization until the end of induced remission therapy (24 weeks) and maintenance therapy (56 weeks) | 
| The changes of biomarkers related to Takayasu's disease at the end of 24 weeks and 56 weeks compared to the baseline, including the whole blood cell RNA transcripts, and gene epigenetics. |  | From the date of randomization until the end of induced remission therapy (24 weeks) and maintenance therapy (56 weeks) | 
| Radiological changes including Magnetic Resonance Angiography or Computed Tomography Angiography at the end of 24 weeks and 56 weeks compared to the baseline |  | From the date of randomization until the end of induced remission therapy (24 weeks) and maintenance therapy (56 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Takayasu Arteritis, Leflunomide