Cyclophosphamide and Azathioprine vs Tacrolimus in Antisynthetase Syndrome-related Interstitial Lung Disease : Multicentric Randomized Phase III Trial
试验速览
- 阶段
- 3 期
- 入组人数
- 76
- 试验地点
- 1
- 主要终点
- Progression free survival
研究概览
简要总结
"Antisynthetase syndrome (ASS) is one of the most severe inflammatory myopathy (IM), due to pulmonary involvement (interstitial lung disease, ILD). Until now, the most commonly used immunosuppresive therapy in Europe is Cyclophosphamide followed by different immunosuppressive drugs as maintenance therapy, including Azathioprine (and so called " European Strategy "). In the USA however, the first-line immunosuppressive treatment is Tacrolimus (so called " American Strategy "). None of these two different strategies has ever been studied prospectively, and there is no clear comparison of short and long-term treatment efficacy and tolerance. Thus, there are yet no evidences helping the clinicians in the therapeutic management of patients with ASS-related ILD.
The aim of this study is therefore to compare both strategies as first line treatments or in relapsing patients : CATR.PAT study is a 52 weeks, randomized, comparative, controlled, open-labeled, phase III, therapeutic clinical trial, comparing two treatment strategies."
详细描述
"During the study period, according to randomization into two groups (n=38 patients, respectively), patients will receive either:
- Group 1 & 2 : 3 IV pulses of Methylprednisolone (7.5 mg/kg/day followed by tapering doses of oral Prednisone, started at 1 mg/kg/day from D4 to M12
In association with :
- Group 1 : European Standard of care :
6 IV pulses of Cyclophosphamide (1000 mg) followed from M5 to M12 by oral Azathioprine (2 mg/kg/day), with a maximum of 150 mg/d)
- Group 2 : American Strategy Tacrolimus is given orally from M0 to M12 (started at the initial dose of 2x2mg/d). Tacrolimus doses are regularly adapted to its serum concentration to reach 5-15 ng/ml."
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
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent
- •Affiliation to the Social security system
- •Diagnosis of ASS: positive test for any of the 5 anti-tRNA synthetase antibodies routinely tested (ELISA, Luminex or Linear-dot), including anti-Jo-1, anti-PL7, anti-PL12, anti-EJ and anti-OJ.
- •Diagnosis of ILD-related ASS: interstitial lung disease on HRCT.
- •Moderate to severe ILD on PFT : FVC < 80% and or cDLCO < 70%
- •beta-HCG test negative or negative uterine echography (for women of child bearing potential)
- •Women of childbearing potential must have an oral contraception (macroprogestatifs) during all the duration of study treatment and 12 months after the last dose of study treatment
- •Males who are sexually active with women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of study treatment and 6 months after the last dose of study treatment
排除标准
- •Pregnancy and/or breast feeding
- •Others contraindications to the treatments, including hypersensitivity to the drug (including excipient and active compounds), medical contraception contraindications, severe renal failure, severe hepatic insufficiency and severe psychiatric disorders. Specific contraindications are listed for each experimental medication in Table 6 (according to updated Summary of product characteristics, see Appendix 8)
- •Fever or active bacterial infection (ie. septicemia, pneumopathy, pyelonephritis, acute prostatitis ...), or parasitic infection (ie. Anguillulosis ...),or fungal infection (ie. Invasive pulmonary aspergillosis ...), or viral infection (HIV seropositivity, Active Tuberculosis, active B/C viral hepatitis, CMV, active EBV...)
- •Active neoplasm
- •Previous inefficacy of Cyclophosphamide, Azathioprine or Tacrolimus, not related to adhesion problems.
- •Previous use of 3 daily IV steroids < 3 months before patient's enrollment.
- •ASS-related ILD worsening or relapse under Prednisone > 0.5 mg/kg/day
- •Previous use of Cyclophosphamide, Azathioprine or Tacrolimus in the last 6 months.
- •Severe ASS requiring ICU (respiratory disease, myocarditis), plasma exchange or IV-Ig.
- •Positivity of auto-antibodies associated to Systemic Sclerosis (anti-Telomerase, anti-Centromères, anti-Polymerase III).
- •Patients with QTc > 450 msec
- •Patients with history of long QT syndrome (including familial) or ventricular arrhythmias
- •Concomitant use of drugs prolonging QT / QTc (list of treatments in annex)
- •Hypokalemia
- •Patients with pulmonary hypertension detected on echocardiography during the screening/selection visit (systolic pulmonary artery pressure (PAP) was 37-50 mmHg, and/or tricuspid regurgitation velocity 2.8-3.4 ms-1) are excluded.
研究组 & 干预措施
European strategy
3 IV pulses of Methylprednisolone (7.5 mg/kg/day followed by tapering doses of oral Prednisone, started at 1 mg/kg/day from D4 to M12
In association with:
6 IV pulses of Cyclophosphamide (1000mg) followed from M5 to M12 by oral Azathioprine (2mg/kg/day), with a maximum of 150mg/day
干预措施: Cyclophosphamide and azathioprine (Drug)
American strategy
3 IV pulses of Methylprednisolone (7.5 mg/kg/day followed by tapering doses of oral Prednisone, started at 1 mg/kg/day from D4 to M12
In association with:
Tacrolimus given orally from M0 to M12 (started at the initial dose of 2x2mg/day). Tacrolimus doses are regularly adapted to its serum concentration to reach 5-15ng/mL.
干预措施: Tacrolimus (Drug)
结局指标
主要结局
Progression free survival
时间窗: From baseline to 12 months
Compare the efficacy of Cyclophosphamide and Azathioprine vs Tacrolimus in patients with ASS related-ILD Time from the initiation of treatment to the first event related to ASS related-ILD (progression free survival)
次要结局
- Variation of the six minute walk tests(at baseline, 3 months, 6 months, 9 months and 12 months)
- Forced Vital Capacity (FVC)(at baseline, 3 months, 6 months, 9 months and 12 months)
- Diffusing Lung Carbon Monoxyde Capacity (cDLCO)(at baseline, 3 months, 6 months, 9 months and 12 months)
- Rate of pulmonary improvement(at baseline, 3 months, 6 months, 9 months and 12 months)
- Quality of Life with SF-36 scale(Baseline, 6 months, 12 months)
- Time to extra-pulmonary improvement(at each visits)
- Treatments tolerance(At every visit)
- Treatment Efficacy(at every visit)
- Rate of extra-pulmonary improvement(at baseline and 12 months)