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
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 116
- 试验地点
- 6
- 主要终点
- Achievement of clinical remission at week 24
研究概览
简要总结
To investigate the efficacy and safety of Leflunomide (LEF) versus placebo combined with prednisone for active Takayasu arteritis (TAK) in Chinese population.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Participants were assigned randomly (1:1) to treatment with LEF or placebo according to a computer-generated blocked randomization list. The randomization list, which assigns a unique randomization number to each treatment, was generated and kept sealed by a randomization administrator (independent of the trial conduct and data analysis). Randomization was masked to patients, investigators, clinical outcome monitors, project managers and statisticians. The packaging of the LEF and placebo was identical with labelled randomization number. For emergency use, investigators were given a sealed opaque envelope for each randomization number. If an envelope was opened, the time, date and reason for opening had to be recorded on the envelope and signed by the investigator. At the end of the trial, all envelopes were returned to the principal investigator unopened to confirm that masking had been maintained throughout the trial.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Leflunomide group
For the first 24 weeks, patients in the LEF group were treated with prednisone (0.6mg/kg/d, p.o.) and LEF (20mg/d, p.o.). The initial dose of prednisone was maintained for 4 weeks and then tapered by 5.0 mg every 2 weeks. The tapering of prednisone dose was determined by the investigators based on their assessment of disease activity. Two investigators formulated a tapering plan for the same time. If there were differences between the 2 investigators' perspectives, a third experienced senior rheumatologist (Lindi Jiang) made the final decision. Once the prednisone dose was reduced to 10 mg/d, this dose was maintained to the end of week 52.
By week 24, if clinical remission had been achieved, the patients proceeded to maintenance therapy with LEF (20 mg/day) from week 25. If the patient did not meet the criteria for clinical remission, unblinding was carried out: patients in the LEF group discontinued the study.
干预措施: Leflunomide(LEF) (Drug)
Leflunomide group
For the first 24 weeks, patients in the LEF group were treated with prednisone (0.6mg/kg/d, p.o.) and LEF (20mg/d, p.o.). The initial dose of prednisone was maintained for 4 weeks and then tapered by 5.0 mg every 2 weeks. The tapering of prednisone dose was determined by the investigators based on their assessment of disease activity. Two investigators formulated a tapering plan for the same time. If there were differences between the 2 investigators' perspectives, a third experienced senior rheumatologist (Lindi Jiang) made the final decision. Once the prednisone dose was reduced to 10 mg/d, this dose was maintained to the end of week 52.
By week 24, if clinical remission had been achieved, the patients proceeded to maintenance therapy with LEF (20 mg/day) from week 25. If the patient did not meet the criteria for clinical remission, unblinding was carried out: patients in the LEF group discontinued the study.
干预措施: Prednisone Acetate Tablets (Drug)
Control Group
For the first 24 weeks, patients in the placebo group received prednisone (0.6mg/kg/d, p.o.) and LEF simulator (2 tablets/d, p.o.). Patients were instructed to take tablets regularly. The initial dose of prednisone was maintained for 4 weeks and then tapered by 5.0 mg every 2 weeks. The tapering of prednisone dose was determined by the investigators based on their assessment of disease activity. Two investigators formulated a tapering plan for the same time. If there were differences between the 2 investigators' perspectives, a third experienced senior rheumatologist (Lindi Jiang) made the final decision. Once the prednisone dose was reduced to 10 mg/d, this dose was maintained to the end of week 52.
By week 24, if clinical remission had been achieved, the patients proceeded to maintenance therapy with LEF (20 mg/day) from week 25. If the patient did not meet the criteria for clinical remission, unblinding was carried out: patients in the placebo group switched to LEF (20 mg/day) .
干预措施: Leflunomide(LEF) (Drug)
Control Group
For the first 24 weeks, patients in the placebo group received prednisone (0.6mg/kg/d, p.o.) and LEF simulator (2 tablets/d, p.o.). Patients were instructed to take tablets regularly. The initial dose of prednisone was maintained for 4 weeks and then tapered by 5.0 mg every 2 weeks. The tapering of prednisone dose was determined by the investigators based on their assessment of disease activity. Two investigators formulated a tapering plan for the same time. If there were differences between the 2 investigators' perspectives, a third experienced senior rheumatologist (Lindi Jiang) made the final decision. Once the prednisone dose was reduced to 10 mg/d, this dose was maintained to the end of week 52.
By week 24, if clinical remission had been achieved, the patients proceeded to maintenance therapy with LEF (20 mg/day) from week 25. If the patient did not meet the criteria for clinical remission, unblinding was carried out: patients in the placebo group switched to LEF (20 mg/day) .
干预措施: Prednisone Acetate Tablets (Drug)
Control Group
For the first 24 weeks, patients in the placebo group received prednisone (0.6mg/kg/d, p.o.) and LEF simulator (2 tablets/d, p.o.). Patients were instructed to take tablets regularly. The initial dose of prednisone was maintained for 4 weeks and then tapered by 5.0 mg every 2 weeks. The tapering of prednisone dose was determined by the investigators based on their assessment of disease activity. Two investigators formulated a tapering plan for the same time. If there were differences between the 2 investigators' perspectives, a third experienced senior rheumatologist (Lindi Jiang) made the final decision. Once the prednisone dose was reduced to 10 mg/d, this dose was maintained to the end of week 52.
By week 24, if clinical remission had been achieved, the patients proceeded to maintenance therapy with LEF (20 mg/day) from week 25. If the patient did not meet the criteria for clinical remission, unblinding was carried out: patients in the placebo group switched to LEF (20 mg/day) .
干预措施: Placebos (Drug)
结局指标
主要结局
Achievement of clinical remission at week 24
时间窗: From the date of randomization until the end of induced remission therapy, assessed up to 24 weeks
Clinical remission is defined as follows: (i) have no systemic symptoms (e.g., fever, fatigue, weight loss); (ii) have no new onset of ischemic symptoms and signs; (iii) have a normal level of erythrocyte sedimentation rate (ESR). If not achieved, the investigator excluded other influencing factors (especially infection), re-measure the ESR after 1 week, and use the re-examined value in the analyses. Subject achieving clinical remission should meet all these criteria above. The clinical remission rate and its difference between LEF and placebo group with 95% confidence interval (CI) at week 24 was estimated by Newcombe-Wilson procedure. If the lower limit of the 95%CI of the difference \>10%, it is considered that the efficacy of LEF is significantly superior to placebo.
次要结局
- Achievement of clinical remission at week 52 in those who switched from placebo to LEF from week 25(From the time of switch from placebo to LEF treatment (week 25), assessed up to week 52)
- Imaging changes at the end of week 24 and week 52 compared to the baseline(From the date of randomization until the end of week 24 and week 52)
- Time to clinical remission(From the date of randomization until the date of first documented clinical remission, assessed up to 24 weeks)
- The mean prednisone dose at week 24(At the end of induced remission therapy, assessed up to 24 weeks)
- Disease recurrence through week 25 to week 52(From the beginning of week 25 to the end of follow up, assessed up to week 52)
- Time to recurrence(from the beginning of achieving clinical remission to the date of the first documented disease recurrence, assessed up to 52 weeks)
- Safety-adverse events(From the date of randomization until the end of this trial, assessed up to 52 weeks)
研究者
Jiang lindi
Chief of Department of Rheumatology
Shanghai Zhongshan Hospital