Takayasu Arteritis Clinical Trial in China
- Conditions
- Takayasu Arteritis
- Interventions
- Registration Number
- NCT02981979
- Lead Sponsor
- Jiang lindi
- 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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 116
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Control Group Leflunomide(LEF) 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) . Leflunomide group Leflunomide(LEF) 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. Leflunomide group Prednisone Acetate Tablets 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. Control Group Prednisone Acetate Tablets 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) . Control Group Placebos 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) .
- Primary Outcome Measures
Name Time Method Achievement of clinical remission at week 24 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.
- Secondary Outcome Measures
Name Time Method 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 Disease recurrence is defined as NIH score ≥2 or not meeting ≥2 criteria for clinical remission.
NIH 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').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 For safety analysis, the incidence and severity of AEs, adverse drug reactions and laboratory values in the LEF and placebo group would be estimated and compared using the χ2 test or Fisher's exact test. The association of an abnormal laboratory index and adverse event with the investigational drug would be evaluated.
Trial Locations
- Locations (6)
The First Hospital of China Medical University
🇨🇳Shenyang, Liaoning, China
Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
🇨🇳Shanghai, Shanghai, China
People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi
🇨🇳Urumqi, Xinjiang, China
Beijing Anzhen Hospital
🇨🇳Beijing, Beijing, China
The first affiliated hospital of Nanchang University
🇨🇳Nanchang, Jiangxi, China
Zhongshan hospital, Fudan University
🇨🇳Shanghai, Shanghai, China