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AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (ACE-IPF)

Primary Purpose

Idiopathic Pulmonary Fibrosis

Status

Terminated

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

warfarin

placebo

About this trial

This is an interventional treatment trial for Idiopathic Pulmonary Fibrosis focused on measuring IPF, Warfarin

Eligibility Criteria

35 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:
1. Worsened dyspnea
2. FVC decreased by >=10% predicted OR
3. DLCO decreased by >=10% absolute OR
4. Reduction of oxygenation saturation >= 5% with or without exertion on a constant oxygen (02) administration
5. 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:
1. 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.
2. Subject has a transplanted organ requiring immunosuppression
3. 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).
4. 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:
1. Current anticoagulation therapy with warfarin
2. Increased risk of bleeding (e.g. uncorrectable inherited or acquired bleeding disorder)
3. Platelet count < 100,000 or hematocrit < 30% or > 55%
4. History of severe gastrointestinal bleeding within 6 months of screening
5. History of cerebral vascular accident (CVA) within 6 months of screening
6. High risks of falls as judged by the PI
7. Surgery or major trauma within the past 30 days
8. Pregnancy, or lack of use of birth control method in women of childbearing age
9. Any condition that, in the determination of the PI, is likely to require anticoagulation therapy during the study.
10. 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.)
11. Patients on prasugrel are excluded. Prasugrel must be stopped for one week prior to starting study drug.

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

warfarin

placebo

Arm Description

Oral warfarin titrated to an international normalization ratio (INR) of 2-3

Oral placebo (1mg or 2.5mg)

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

All Cause Mortality

Change in Forced Vital Capacity (FVC) From Baseline to 16 Weeks

Week-16 change from Baseline

All-cause Hospitalizations

Bleeding Events

Acute Exacerbations of Idiopathic Pulmonary Fibrosis (IPF)

Respiratory-related Hospitalizations

Cardiovascular Mortality or Morbidity

Measured at 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).

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).

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.

Fibrin D-dimer Change From Baseline to 16 Weeks

Biomarker that measures biologic activities in patients as opposed to response.

Full Information

NCT ID

NCT00957242

First Posted

August 10, 2009

Last Updated

July 14, 2014

Sponsor

Duke University

Collaborators

National Heart, Lung, and Blood Institute (NHLBI), Duke Clinical Research Institute

1. Study Identification

Unique Protocol Identification Number

NCT00957242

Brief Title

AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis

Acronym

ACE-IPF

Official Title

AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (ACE-IPF)

Study Type

Interventional

2. Study Status

Record Verification Date

April 2013

Overall Recruitment Status

Terminated

Why Stopped

Excess of mortality in the treatment group created safety concerns.

Study Start Date

October 2009 (undefined)

Primary Completion Date

July 2011 (Actual)

Study Completion Date

July 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Duke University

Collaborators

National Heart, Lung, and Blood Institute (NHLBI), Duke Clinical Research Institute

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Idiopathic Pulmonary Fibrosis

Keywords

IPF, Warfarin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

145 (Actual)

8. Arms, Groups, and Interventions

Arm Title

warfarin

Arm Type

Active Comparator

Arm Description

Oral warfarin titrated to an international normalization ratio (INR) of 2-3

Arm Title

placebo

Arm Type

Placebo Comparator

Arm Description

Oral placebo (1mg or 2.5mg)

Intervention Type

Drug

Intervention Name(s)

warfarin

Other Intervention Name(s)

warfarin sodium

Intervention Description

Oral warfarin (1mg or 2.5mg) titrated to an INR of 2-3.

Intervention Type

Drug

Intervention Name(s)

placebo

Intervention Description

Oral placebo (1mg or 2.5mg)

Primary Outcome Measure Information:

Title

Death, Non-bleeding/Non-elective Hospitalization, or >10% Drop in Forced Vital Capacity

Description

Death, non-bleeding/non-elective hospitalization, or >10% drop in forced vital capacity.

Time Frame

Events up to 48 weeks

Secondary Outcome Measure Information:

Title

All Cause Mortality

Time Frame

maximum of 48 weeks

Title

Change in Forced Vital Capacity (FVC) From Baseline to 16 Weeks

Description

Week-16 change from Baseline

Time Frame

16 weeks

Title

All-cause Hospitalizations

Time Frame

maximum 48 weeks

Title

Bleeding Events

Time Frame

maximum of 48 weeks

Title

Acute Exacerbations of Idiopathic Pulmonary Fibrosis (IPF)

Time Frame

maximum of 48 weeks

Title

Respiratory-related Hospitalizations

Time Frame

maximum 48 weeks

Title

Cardiovascular Mortality or Morbidity

Description

Measured at 48 Weeks

Time Frame

maximum of 48 weeks

Title

Change in 6-minute Walk Distance (6MWD)

Description

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).

Time Frame

Change from baseline to last visit (maximum of 48 weeks)

Title

Total Score St. George's Respiratory Questionnaire (SGRQ)

Description

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).

Time Frame

Week 16 Change from Baseline

Title

Change in Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) From Baseline to 16 Weeks

Description

The DLCO measures the partial pressure difference between inspired and expired carbon monoxide.

Time Frame

Week 48 / Final Visit

Title

Fibrin D-dimer Change From Baseline to 16 Weeks

Description

Biomarker that measures biologic activities in patients as opposed to response.

Time Frame

maximum of 48 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

35 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials: