Clinical trial NCT02981979: Takayasu Arteritis Clinical Trial in China
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Takayasu Arteritis
Keywords: Takayasu Arteritis
Leflunomide
Lead sponsor: Shanghai Zhongshan Hospital
Sponsor class: OTHER
First posted: 2016-12-05
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To investigate the efficacy and safety of Leflunomide (LEF) versus placebo combined with prednisone for active Takayasu arteritis (TAK) in Chinese population.

Detailed description: 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.

Primary outcomes:
measure: Achievement of clinical remission at week 24
timeFrame: From the date of randomization until the end of induced remission therapy, assessed up to 24 weeks
Secondary outcomes:
measure: Time to clinical remission
timeFrame: From the date of randomization until the date of first documented clinical remission, assessed up to 24 weeks
measure: The mean prednisone dose at week 24
timeFrame: At the end of induced remission therapy, assessed up to 24 weeks
measure: Achievement of clinical remission at week 52 in those who switched from placebo to LEF from week 25
timeFrame: From the time of switch from placebo to LEF treatment (week 25), assessed up to week 52
measure: Disease recurrence through week 25 to week 52
timeFrame: From the beginning of week 25 to the end of follow up, assessed up to week 52
measure: Time to recurrence
timeFrame: from the beginning of achieving clinical remission to the date of the first documented disease recurrence, assessed up to 52 weeks
measure: Imaging changes at the end of week 24 and week 52 compared to the baseline
timeFrame: From the date of randomization until the end of week 24 and week 52
measure: Safety-adverse events
timeFrame: From the date of randomization until the end of this trial, assessed up to 52 weeks
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Anzhen Hospital
state: Beijing
city: Nanchang
country: China
facility: The first affiliated hospital of Nanchang University
state: Jiangxi
city: Shenyang
country: China
facility: The First Hospital of China Medical University
state: Liaoning
city: Shanghai
country: China
facility: Zhongshan hospital, Fudan University
state: Shanghai
city: Shanghai
country: China
facility: Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
state: Shanghai
city: Urumqi
country: China
facility: People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi
state: Xinjiang
Study officials:
affiliation: Fudan University
name: Lindi Jiang, Doctor
role: STUDY_DIRECTOR
References: