AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (ACE-IPF)
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 145
- 试验地点
- 22
- 主要终点
- Death, Non-bleeding/Non-elective Hospitalization, or >10% Drop in Forced Vital Capacity
研究概览
简要总结
This study will test the effectiveness of warfarin in patients with IPF. Approximately 256 patients will be randomized 1:1 to either warfarin or placebo. Patients will return at week 1 for a safety review and every 16 weeks for 48 weeks. The primary endpoint in the study is the time to either death, non-bleeding/non-elective hospitalization, or a drop of greater than 10% in forced vital capacity (FVC) from baseline.
详细描述
Study design:
ACE-IPF was a double-blind, randomized, placebo-controlled trial of an oral warfarin dose adjusted to an international normalized ratio (INR) response of 2.0 to 3.0, compared with a sham dose-adjusted placebo. The trial was originally designed as an event-driven study with a treatment period of up to 144 weeks. Given the slow rate of recruitment and higher than anticipated event rates seen in another Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet) trial, the protocol was modified to have a maximum treatment period of 48 weeks after eleven patients were enrolled in the study. Participants were to be seen at screening, baseline, and at 16, 32, and 48 weeks after enrollment.
Outcome measures:
The primary outcome was a composite endpoint based on the time to all-cause mortality; non-elective, non-bleeding hospitalization; or a decrease in the absolute FVC ≥10% from baseline value. Secondary outcome measures included rates of mortality, hospitalization, respiratory-related hospitalization, acute exacerbation, bleeding, cardiovascular events, and changes over time in FVC, six-minute walk test distance, diffusing capacity of lung for carbon monoxide (DLCO), plasma fibrin D-dimer levels, and quality of life (QOL) assessments.
Data Analysis Continuous variables at baseline were expressed as means (standard deviations) and medians (25th and 75th percentiles). Categorical variables at baseline were expressed as counts and percentages. Unadjusted estimates of event rates for time-to-event variables were computed using the Kaplan-Meier estimator with comparisons based on the log-rank test statistic. The primary hypothesis was tested using a Cox proportional hazards regression model, comparing the treatment effect on the primary composite endpoint. Pre-specified covariates in this model included an indicator variable for the treatment group and the DLCO measurement from the baseline assessment.
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
- 35 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of IPF
- •Age between 35 and 80, inclusive
- •Capable of understanding and signing consent
- •Progression despite conventional therapy (standard of care). Progression defined as:
- •Worsened dyspnea
- •FVC decreased by >=10% predicted OR
- •DLCO decreased by >=10% absolute OR
- •Reduction of oxygenation saturation >= 5% with or without exertion on a constant oxygen (02) administration
- •Worsened radiographic findings (chest x-ray or high-resolution computed tomography)
排除标准
- •Current enrollment in another investigational protocol
- •Current treatment with an investigational drug (i.e., participating in an active investigational drug protocol) within the previous 4 weeks or 5 times the half-life of the investigational agent, whichever is longer, prior to screening
- •Subject is actively listed for lung transplantation at the time of enrollment
- •Subjects who will not be able to perform/complete the study, in the judgment of the physician investigator or coordinator, for at least 3 months. For example:
- •Subject has current signs or symptoms of severe, progressive or uncontrolled comorbid illnesses such as: renal, hepatic, hematologic, gastrointestinal, endocrine, cardiac, neurologic, or cerebral disease, or any laboratory abnormality which would pose/suggest a risk to the subject during participation in the study.
- •Subject has a transplanted organ requiring immunosuppression
- •History of substance abuse (drugs or alcohol) within the 2 years prior to screening, history of noncompliance to medical regimens, inability or unwillingness to perform INR monitoring, or other condition/circumstance that could interfere with the subject's adherence to protocol requirements (e.g. psychiatric disease, lack of motivation, travel, etc).
- •Have any known active malignancy or have a history of malignancy within the previous 2 years (an example of an exception is a non-melanoma skin cancer that has been treated with no evidence of recurrence for at least 3 months) that might increase the risk of bleeding.
- •Estimated life expectancy < 12 months due to a non-pulmonary cause.
- •Subject has another respiratory disease that is predominant (as judged by the PI) in addition to IPF.
- •Anticoagulation-related exclusions include:
- •Current anticoagulation therapy with warfarin
- •Increased risk of bleeding (e.g. uncorrectable inherited or acquired bleeding disorder)
- •Platelet count < 100,000 or hematocrit < 30% or > 55%
- •History of severe gastrointestinal bleeding within 6 months of screening
- •History of cerebral vascular accident (CVA) within 6 months of screening
- •High risks of falls as judged by the PI
- •Surgery or major trauma within the past 30 days
- •Pregnancy, or lack of use of birth control method in women of childbearing age
- •Any condition that, in the determination of the PI, is likely to require anticoagulation therapy during the study.
- •Clopidogrel and aspirin combination therapy for > 30 days duration is exclusionary.
- •(Aspirin monotherapy [81-325 mg daily] or clopidogrel monotherapy are acceptable. Combination clopidogrel and aspirin <=81mg/day for ≤30 days is also acceptable. NSAIDS are discouraged; acetaminophen may be substituted.)
- •Patients on prasugrel are excluded. Prasugrel must be stopped for one week prior to starting study drug.
研究组 & 干预措施
warfarin
Oral warfarin titrated to an international normalization ratio (INR) of 2-3
干预措施: warfarin (Drug)
placebo
Oral placebo (1mg or 2.5mg)
干预措施: placebo (Drug)
结局指标
主要结局
Death, Non-bleeding/Non-elective Hospitalization, or >10% Drop in Forced Vital Capacity
时间窗: Events up to 48 weeks
Death, non-bleeding/non-elective hospitalization, or \>10% drop in forced vital capacity.
次要结局
- All Cause Mortality(maximum of 48 weeks)
- Change in Forced Vital Capacity (FVC) From Baseline to 16 Weeks(16 weeks)
- All-cause Hospitalizations(maximum 48 weeks)
- Change in 6-minute Walk Distance (6MWD)(Change from baseline to last visit (maximum of 48 weeks))
- Total Score St. George's Respiratory Questionnaire (SGRQ)(Week 16 Change from Baseline)
- Change in Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) From Baseline to 16 Weeks(Week 48 / Final Visit)
- Fibrin D-dimer Change From Baseline to 16 Weeks(maximum of 48 weeks)
- Bleeding Events(maximum of 48 weeks)
- Acute Exacerbations of Idiopathic Pulmonary Fibrosis (IPF)(maximum of 48 weeks)
- Respiratory-related Hospitalizations(maximum 48 weeks)
- Cardiovascular Mortality or Morbidity(maximum of 48 weeks)