AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis

Study Overview
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Brief Summary
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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.

Detailed Description
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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. Randomization: Subjects were randomly assigned to study arms in a 1:1 ratio, using a permuted-block design with varying block sizes, to receive either warfarin or matched placebo. Subjects were stratified by clinical center and a DLCO threshold of 35% of predicted. Randomization lists were generated by the study data coordinating center (DCC) and provided to a phone- and web-enabled registration system (Almac Clinical Services, Inc.) that allowed sites to enroll subjects and receive study kits while keeping the study team and subjects blinded to treatment assignment. INR testing and monitoring: Study subjects were provided two strengths of warfarin tablets (1 mg and 2.5 mg) or matching placebos. Subjects measured their INR with encrypted meters (INRatio®, Alere, San Diego, CA) at least weekly. Home monitoring was validated by plasma INR measurement at the week 1 and 16 visits. Individual INR meters and test strips were replaced and subjects were reinstructed if meter INR readings varied by more than 30% from the laboratory INR. Efficacy of home INR measures were determined by time-in-target INR range of all patients, calculated on the basis of linear interpolation, 12 after excluding readings taken at baseline, during initial warfarin titration (until INR ≥ 2.0), study drug interruption, or following the discontinuation of study drug.

Official Title
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AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (ACE-IPF)

Conditions
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Idiopathic Pulmonary Fibrosis

Intervention / Treatment
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* Drug: warfarin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: warfarin<br>Oral warfarin titrated to an international normalization ratio (INR) of 2-3 | Drug: warfarin<br>* Oral warfarin (1mg or 2.5mg) titrated to an INR of 2-3.<br>* Other names: warfarin sodium;|
| Placebo Comparator: placebo<br>Oral placebo (1mg or 2.5mg) | Drug: placebo<br>* Oral placebo (1mg or 2.5mg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death, Non-bleeding/Non-elective Hospitalization, or >10% Drop in Forced Vital Capacity | Death, non-bleeding/non-elective hospitalization, or >10% drop in forced vital capacity. | Events up to 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Cause Mortality |  | maximum of 48 weeks | 
| Change in Forced Vital Capacity (FVC) From Baseline to 16 Weeks | Week-16 change from Baseline | 16 weeks | 
| All-cause Hospitalizations |  | maximum 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 | Measured at 48 Weeks | maximum of 48 weeks | 
| Change in 6-minute Walk Distance (6MWD) | The 6MWD is a measure of exercise tolerance. Change in exercise tolerance is calculated at the latest time point (up to 48 weeks) minus the earliest time point (at baseline). | Change from baseline to last visit (maximum of 48 weeks) | 
| Total Score St. George's Respiratory Questionnaire (SGRQ) | The SGRQ is a quality of life measurement used to assess respiratory well being with a 0*-100 range (*indicates better health--lower is better). | Week 16 Change from Baseline | 
| Change in Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) From Baseline to 16 Weeks | The DLCO measures the partial pressure difference between inspired and expired carbon monoxide. | Week 48 / Final Visit | 
| Fibrin D-dimer Change From Baseline to 16 Weeks | Biomarker that measures biologic activities in patients as opposed to response. | maximum of 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IPF, Warfarin