takayasu arteritis clinical trial in china

Conditions: Takayasu Arteritis

Summary: to investigate the efficacy and safety of leflunomide (lef) versus placebo combined with prednisone for active takayasu arteritis (tak) in chinese population.

takayasu arteritis (tak) is a rare form of large-vessel vasculitis, characterized by immune -induced vascular inflammation, resulting in the stenosis and occlusion of blood vessels \[1\]. tak is observed predominantly in asian females under 40 years of age \[2, 3\]. the stenosis or occlusion of blood vessels can cause severe ischemic events (e.g., acute myocardial infarction, stroke, death) involving multiple organs. patients with tak experience impaired quality of life \[4\] and face a significantly higher risk of death compared with that in the sex- and age-matched general population, with a standardized mortality ranging from 2.7 to 17.3 \[5, 6, 7\]. thus, timely and efficacious treatment is important to improve the prognosis in such a young population. glucocorticoids (gcs) are the first-line therapy for active tak \[8, 9\]. high-dose gcs are initially efficacious. however, disease recurrence can occur in approximately 60% patients during the gcs tapering \[10, 11\]. prolonged use of gcs is associated with significant toxicity, including glucose-metabolism disorders, cardiovascular adverse events (aes), and osteoporosis \[12, 13\]. therefore, immunosuppressive therapy is required to minimize the dose and duration of gc exposure \[8, 9\]. conventional immunosuppressants have been recommended as gc-tapering agents for active tak, whereas biological agents are recommended in refractory cases \[8, 9\]. most previous studies focused on tak treatment have been observational, only five randomized clinical trials (rcts) are found, among which, just one study reported the effect of conventional immunosuppressants mycophenolate \[14, 15, 16, 17, 18\]. thus, high-quality evidence to support therapeutic options of conventional immunosuppressants is very limited. leflunomide (lef) is a conventional immunosuppressant \[19\], which has shown satisfied gc-tapering effects in the treatment of giant cell arteritis, another large vessel vasculitis, in several observational studies \[20, 21, 22\]. in 2012, the first open-label study of 14 tak patients demonstrated that 70% of patients could achieve at least partial clinical remission, and the gc dose could be reduced by 50% during lef treatment \[23\]. since then, several observational cohort or case-control studies have reported the efficacy of lef for active tak \[24, 25, 26, 27, 28, 29\]. a most recent study reported a comparable complete response rate of lef (78%) versus adalimumab (88%) at 15-month follow-up \[30\]. thus, lef would be a promising alternative treatment for tak, but evidence from rcts is lacking. we conducted this multicenter, randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of lef versus placebo combined with prednisone for active tak, namely "takayasu arteritis clinical trial in china" (tactic; clinicaltrials.gov identifier: nct02981979).

Eligibility criteria:
inclusion criteria i. male or females aged 18-65 years diagnosed with tak according to the classification criteria set by the american college of rheumatology (acr) in 1990; ii. with active disease within the last 3 months, meeting at least two of the following conditions: 1. new vascular ischemic manifestations/physical signs or systemic symptoms; 2. evaluated erythrocyte sedimentation rate (esr) or high-sensitivity c reactive protein (hs-crp) ≥6 mg/l or c reactive protein (crp) ≥10 mg/l without other confounding factors (e.g., infection); 3. active vascular inflammation as indicated by contrast-enhanced computed tomography angiography (cta), magnetic resonance angiography (mra), color doppler ultrasonography or positron emission tomography/ct (pet/ct); iii. individuals should not receive lef within 3 months before screening; iv. for individuals who received cyclophosphamide before screening, cyclophosphamide should be discontinued for ≥8 weeks; for patients who received a biological agent before screening, biological agents (e.g., tocilizumab, rituximab, and inhibitors of tumor necrosis factor) should be discontinued for ≥12 weeks; v. for patients who were taking prednisone (or its equivalent) before screening, the dose should be ≤0.6 mg/kg/day and the dose should be stable for ≥4 weeks; vi. pregnancy should not be planned and a pregnancy test should be negative. exclusion criteria i. individuals who had only vascular dilatation or aneurysm formation; ii. individuals who had received revascularization surgery within the previous 3 months; iii. individuals with severe organ dysfunction meeting at least one of the following: 1. heart dysfunction: new york heart association grade iv; 2. renal dysfunction: estimated glomerular filtration rate ≤60 ml/min; 3. liver dysfunction: child-pugh grade ≥2; 4. neurologic severe ischemic event: amaurosis on 3 consecutive days, acute cerebral infarction, or cerebral hemorrhage; 5. uncontrolled blood pressure \>160/100 mmhg; iv. individuals had at least one following abnormal laboratory test results: (1) alanine aminotransferase or aspartate transaminase ≥1.5-fold of the upper limit of normal in serum; (2) white blood cell count ≤4×109/l; (3) platelet count ≤100×109/l; (4) hemoglobin ≤85 g/l; v. individuals had other types of autoimmune disease or uncontrolled asthma who need prednisone ≥10 mg/day, a history of malignant tumor or any serious acute/chronic infection, including positivity for hepatitis b surface antigen, hepatitis c antibody, or clinical/radiological/laboratory evidence of active tuberculosis; vi. individuals who were allergic to any of the investigational drugs; vii. individuals had at least one of the following unacceptable treatments or medications: 1. previous treatment with lef for ≥3 months but not efficacious; 2. planning to receive an attenuated vaccine during the study period; 3. planning to undergo (or have undergone) organ transplantation.

Keywords: takayasu arteritis leflunomide