AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (ACE-IPF)

This study has been terminated.
(Excess of mortality in the treatment group created safety concerns.)
Sponsor:
Collaborators:
Duke Clinical Research Institute
Information provided by (Responsible Party):
Duke University
ClinicalTrials.gov Identifier:
NCT00957242
First received: August 10, 2009
Last updated: July 14, 2014
Last verified: April 2013
  Purpose

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.


Condition Intervention Phase
Idiopathic Pulmonary Fibrosis
Drug: warfarin
Drug: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (ACE-IPF)

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • Death, Non-bleeding/Non-elective Hospitalization, or >10% Drop in Forced Vital Capacity [ Time Frame: Events up to 48 weeks ] [ Designated as safety issue: Yes ]
    Death, non-bleeding/non-elective hospitalization, or >10% drop in forced vital capacity.


Secondary Outcome Measures:
  • All Cause Mortality [ Time Frame: maximum of 48 weeks ] [ Designated as safety issue: Yes ]
  • Change in Forced Vital Capacity (FVC) From Baseline to 16 Weeks [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
    Week-16 change from Baseline

  • All-cause Hospitalizations [ Time Frame: maximum 48 weeks ] [ Designated as safety issue: No ]
  • Bleeding Events [ Time Frame: maximum of 48 weeks ] [ Designated as safety issue: Yes ]
  • Acute Exacerbations of Idiopathic Pulmonary Fibrosis (IPF) [ Time Frame: maximum of 48 weeks ] [ Designated as safety issue: No ]
  • Respiratory-related Hospitalizations [ Time Frame: maximum 48 weeks ] [ Designated as safety issue: No ]
  • Cardiovascular Mortality or Morbidity [ Time Frame: maximum of 48 weeks ] [ Designated as safety issue: No ]
    Measured at 48 Weeks

  • Change in 6-minute Walk Distance (6MWD) [ Time Frame: Change from baseline to last visit (maximum of 48 weeks) ] [ Designated as safety issue: No ]
    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) [ Time Frame: Week 16 Change from Baseline ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 48 / Final Visit ] [ Designated as safety issue: No ]
    The DLCO measures the partial pressure difference between inspired and expired carbon monoxide.

  • Fibrin D-dimer Change From Baseline to 16 Weeks [ Time Frame: maximum of 48 weeks ] [ Designated as safety issue: No ]
    Biomarker that measures biologic activities in patients as opposed to response.


Enrollment: 145
Study Start Date: October 2009
Study Completion Date: July 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: warfarin
Oral warfarin titrated to an international normalization ratio (INR) of 2-3
Drug: warfarin
Oral warfarin (1mg or 2.5mg) titrated to an INR of 2-3.
Other Name: warfarin sodium
Placebo Comparator: placebo
Oral placebo (1mg or 2.5mg)
Drug: placebo
Oral placebo (1mg or 2.5mg)

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.

  Eligibility

Ages Eligible for Study:   35 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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:

    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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00957242

  Show 22 Study Locations
Sponsors and Collaborators
Duke University
Duke Clinical Research Institute
Investigators
Study Chair: Galen Toews, MD University of Michigan
Study Director: Gail Weinmann, MD National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Kevin Brown, MD National Jewish Health
Principal Investigator: Rob Kaner, MD Weill Medical College at Cornell University
Principal Investigator: Talmadge King, MD University of California, San Francisco
Principal Investigator: Joe Lasky, MD Tulane University School of Medicine
Principal Investigator: James Loyd, MD Vanderbilt University
Principal Investigator: Fernando Martinez, MD University of Michigan
Principal Investigator: Imre Noth, MD University of Chicago
Principal Investigator: Ganesh Raghu, MD University of Washington
Principal Investigator: Jesse Roman, MD Emory University
Principal Investigator: Jay Ryu, MD Mayo Clinic
Principal Investigator: Joseph Lynch, MD University of California, Los Angeles
Principal Investigator: Kevin Anstrom, PhD Duke University
Principal Investigator: Joao deAndrade, MD University of Alabama at Birmingham
Principal Investigator: Jeffrey Chapman, MD The Cleveland Clinic
Principal Investigator: Lake Morrison, MD Duke University
Principal Investigator: Michael Kallay, MD Highland Hospital
Principal Investigator: Steven Sahn, MD Medical University of South Carolina
Principal Investigator: Marilyn Glassberg, MD University of Miami
Principal Investigator: Milton Rossman, MD University of Pennsylvania
Principal Investigator: John Fitzgerald, MD University of Texas
Principal Investigator: Mary Beth Scholand, MD University of Utah
Principal Investigator: Neil Ettinger, MD St Luke's Hospital
Principal Investigator: Danielle Antin-Ozerkis, MD Yale University
  More Information

Additional Information:
No publications provided by Duke University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT00957242     History of Changes
Other Study ID Numbers: Pro00017156, 5U10HL080413-05, 671
Study First Received: August 10, 2009
Results First Received: March 4, 2013
Last Updated: July 14, 2014
Health Authority: United States: Federal Government

Keywords provided by Duke University:
IPF
Warfarin

Additional relevant MeSH terms:
Fibrosis
Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Idiopathic Interstitial Pneumonias
Lung Diseases, Interstitial
Anticoagulants
Warfarin
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 23, 2014