Takayasu Arteritis Clinical Trial in China

Comparison of the Efficacy and Safety of Leflunomide Versus Placebo Combined With Basic Prednisone Therapy in Patients With Active Takayasu Arteritis: a Randomized Double-blind Controlled Clinical Trial

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).

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.