A Single-center, Randomized, Double-blind, Controlled Study Comparing the Efficacy and Safety of Pirfenidone Versus Placebo in the Treatment of Takayasu Arteritis on the Basis of Conventional Immunosuppressive Therapy
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 92
- 主要终点
- the effectiveness of pirfenidone in the treatment of Takayasu arteritis compared to the placebo
研究概览
简要总结
Takayasu arteritis is a severe vasculitis which could lead to significant disability and even death. While standard anti-inflammatory treatments can manage the systemic inflammation, they failed to stop a key driver of the disease: vascular fibrosis. This fibrosis could result in blood vessels thickening and narrowing, which continues to progress in many patients.
To tackle this critical treatment gap, the present project explores a new strategy. Building on pirfenidone's success in treating fibrosis in organs just like lungs and liver, along with promising early observations from our center, investigators believe adding this anti-fibrotic drug to standard therapy could improve vessel injury directly.
Therefore, investigators plan to conduct a clinical trial comparing pirfenidone with placebo in patients with Takayasu arteritis. The goal is to determine if this approach can successfully improve vascular injury and patient outcomes ultimately.
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)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients who have signed the informed consents and meet the ACR 2022 classification criteria for Takayasu arteritis.
- •Male or female, age between 18 and 60 years.
- •Female patients must have a negative serum or urine pregnancy test and do not have pregnancy plans during the study period.
- •Within the 3 months prior to enrollment, the patient's treatment regimen must consist of glucocorticoids and immunosuppressants (methotrexate). Biological agents (IL-6R, TNF, or monoclonal antibody) might be used based on clinical need. Other targeted therapies (such as CD20 monoclonal antibodies, JAK inhibitors, etc.) or cell-based therapies (such as CAR-T or stem cell therapy) are not permitted.
- •During the 6-month follow-up period, the dosage and frequency of existing methotrexate and biologics (IL-6R monoclonal antibody, TNF monoclonal antibody, IL17 monoclonal antibody) must remain unchanged, except for adjustments of glucocorticoid doses based on clinical condition.
- •After 3 months of the above combination glucocorticoid and immunosuppressants, patients must achieve remission of disease activity (NIH score <2) and meet at least 3 of the following 5 criteria:
- •i. Thickening of the affected vessel wall accompanied by luminal stenosis validated by angiographic examination.
- •ii. Carotid ultrasound showing medium-to-high echogenicity of the carotid artery wall.
- •iii. Progression in the thickness of the affected arterial wall compared to previous 3 months, with or without progression of luminal stenosis.
- •iv. Improvement in the thickness of the affected arterial wall of <10% compared to previous 3 months.
- •v. Within the 3 months prior to enrollment, the occurrence of new vascular ischemic symptoms or ischemic events, or worsening of pre-existing vascular ischemic symptoms. The ischemic symptoms or events must meet at least one of the criteria listed in the table below: Category (Criterion) Vascular Ischemic Signs
- •New emerged vascular bruits (carotid, subclavian, or renal arteries).
- •Newly emerged absent pulses (carotid, subclavian, brachial, radial, femoral, or dorsalis pedis arteries).
- •New emerged systolic blood pressure difference ≥10 mmHg between left and right arms.
- •New emerged systolic blood pressure difference ≥30 mmHg between ipsilateral upper and lower limbs.
- •Intermittent claudication in upper or lower limbs.
- •For non-hypertensive patients, blood pressure elevation to >140/90 mmHg.
- •For hypertensive patients, an increase in diastolic blood pressure ≥20 mmHg from baseline.
- •Ischemic angina.
- •Myocardial infarction.
- •Aortic valve insufficiency (moderate or severe).
- •Ischemic stroke.
- •New emerged ischemic symptoms: syncope, visual or auditory abnormalities such as decreased vision, visual field defects, etc.
- •CT cerebral perfusion imaging indicating ischemic or infarcted areas (with a corresponding volume >10 ml detected by CTP software).
- •Renal Radionuclide renogram showing a decrease in glomerular filtration rate over 10%; or an increase in serum creatinine exceeding 50% compared with the baseline.
排除标准
- •Presence of autoimmune diseases or autoinflammatory diseases other than Takayasu arteritis (e.g., systemic lupus erythematosus, ankylosing spondylitis, rheumatoid arthritis, etc.);
- •Use of antifibrotic drugs or drugs with potential antifibrotic properties (such as acetylcysteine, nintedanib, pirfenidone, etc.) within 6 months prior to enrollment, or participation in other clinical trials involving antifibrotic therapies;
- •Impaired liver function (elevated transaminases ALT/AST >2 times the upper limit of normal, or bilirubin exceeding the upper limit of normal), severe renal insufficiency (eGFR <15 mL/min/1.73m²), or requirement for psychotropic medications (excluding sleep medicine for sleep disorders);
- •Any severe, progressive, or uncontrolled concurrent hematological, gastrointestinal, pulmonary, cardiac, neurological, or other medical conditions unrelated to Takayasu arteritis which could pose unpredictable risks, in the investigator's judgment;
- •Allergy to the investigational drug or previous failure of regular pirfenidone treatment for 3 months;
- •Due to pirfenidone's metabolism primarily via cytochrome P450 isoenzymes (particularly CYP1A2), use of CYP1A2 inducers or inhibitors prior to enrollment must be discontinued and avoided throughout the study period; such medications are also prohibited during the study unless deemed medically necessary by the investigator for managing adverse events;
- •History of allergy to MRA contrast agents;
- •Planned vascular surgery during the 6-month follow-up period which may interfere with assessment results.
- •CYP1A2 Inhibitors:
- •Acyclovir, amiodarone, atazanavir, caffeine, cimetidine, ciprofloxacin, enoxacin, famotidine, flutamide, fluvoxamine, lidocaine, lomefloxacin, mexiletine, moclobemide, norfloxacin, ofloxacin, perphenazine, propafenone, ropinirole, tacrine, ticlopidine, tocainide, verapamil
- •CYP1A2 Inducers:
- •Carbamazepine, esomeprazole, griseofulvin, lansoprazole, moricizine, omeprazole, rifampin, ritonavir
研究组 & 干预措施
placebo
干预措施: Placebo (Drug)
pirfenidone
干预措施: Pirfenidone Capsules (Drug)
结局指标
主要结局
the effectiveness of pirfenidone in the treatment of Takayasu arteritis compared to the placebo
时间窗: "From enrollment to the end of treatment at 6 months"
Compared to placebo, the effectiveness of pirfenidone in the treatment of Takayasu arteritis is assessed with a composite endpoint. It indicates both clinical remission and imaging efficacy criterias must be met simultaneously, as follows: Clinical remission should meet all of the following criterias (①-④): * Absence of systemic symptoms such as fever, fatigue, or weight loss; * No new vascular symptoms or signs, and no worsening of pre-existing vascular symptoms; ③ No new ischemic symptoms or signs, and no worsening of pre-existing ischemic symptoms; ④ Normal erythrocyte sedimentation rate (if abnormal, non-disease activity factors must be excluded; a repeat test should be performed for evaluation); Note: If any of the following events occur in the CTCAE 5.0 grade increasing from baseline and reach grade 2 or higher, the case will be directly classified as not remission. These events include: ischemic stroke, syncope, intermittent claudication, and myocardial infarction.
次要结局
- The radiographic response rate of pirfenidone in the treatment of Takayasu arteritis at 6th month, compared to placebo.(From enrollment to the end of treatment at 6 months)
- Compared to placebo, the clinical remission rate of pirfenidone at the end of 6th month in the treatment of Takayasu arteritis.(From enrollment to the end of treatment at 6 months)
- Compared to placebo, the average dose of glucocorticoid at the end of 6th month in pirfenidone, in the treatment of Takayasu arteritis.(From enrollment to the end of treatment at 6 months)
- Compared to placebo, the incidence of ischemic events within 6 months for pirfenidone in the treatment of Takayasu arteritis.(From enrollment to the end of treatment at 6 months)
- Compared to placebo, changes of fibrosis markers (MMP-1, MMP-3, MMPP-9, TIMP-1, etc.) for pirfenidone in the treatment of Takayasu arteritis at the end of 6 months.(From enrollment to the end of treatment at 6 months)
- Compared to placebo， the improvement of quality of life at the end of month 6 with pirfenidone in the treatment of Takayasu arteritis (assessed by SF-36).(From enrollment to the end of treatment at 6 months)