AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (ACE-IPF)

• ClinicalTrials.gov Identifier: NCT00957242
• Recruitment Status: Terminated
• First Posted: August 12, 2009
• Results First Posted: October 21, 2013
• Last Update Posted: July 23, 2014
• Sponsor: Duke University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Duke Clinical Research Institute
• Information provided by (Responsible Party): Duke University

Tracking Information

• First Submitted Date: August 10, 2009
• First Posted Date: August 12, 2009
• Results First Submitted Date: March 4, 2013
• Results First Posted Date: October 21, 2013
• Last Update Posted Date: July 23, 2014
• Study Start Date: October 2009
• Actual Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 9, 2013)

Death, Non-bleeding/Non-elective Hospitalization, or >10% Drop in Forced Vital Capacity [ Time Frame: Events up to 48 weeks ]

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

• Original Primary Outcome Measures (submitted: August 10, 2009): Time to death, non-bleeding/non-elective hospitalization, or >10% drop in forced vital capacity. [ Time Frame: Time-to-event (maximum of 144 weeks) ]

Current Secondary Outcome Measures (submitted: August 9, 2013)

• All Cause Mortality [ Time Frame: maximum of 48 weeks ]
• Change in Forced Vital Capacity (FVC) From Baseline to 16 Weeks [ Time Frame: 16 weeks ]
  Week-16 change from Baseline
• All-cause Hospitalizations [ Time Frame: maximum 48 weeks ]
• Bleeding Events [ Time Frame: maximum of 48 weeks ]
• Acute Exacerbations of Idiopathic Pulmonary Fibrosis (IPF) [ Time Frame: maximum of 48 weeks ]
• Respiratory-related Hospitalizations [ Time Frame: maximum 48 weeks ]
• Cardiovascular Mortality or Morbidity [ Time Frame: maximum of 48 weeks ]
  Measured at 48 Weeks
• Change in 6-minute Walk Distance (6MWD) [ Time Frame: Change from baseline to last visit (maximum of 48 weeks) ]
  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 ]
  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 ]
  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 ]
  Biomarker that measures biologic activities in patients as opposed to response.

Original Secondary Outcome Measures (submitted: August 10, 2009)

• All cause mortality [ Time Frame: maximum of 144 weeks ]
• Change in forced vital capacity (FVC) from baseline [ Time Frame: maximum of 144 weeks ]
• All-cause hospitalizations [ Time Frame: maximum 144 weeks ]
• Difference in global ranking [ Time Frame: maximum 144 weeks ]
• Difference in bleeding events [ Time Frame: maximum of 144 weeks ]
• Acute exacerbations of IPF [ Time Frame: maximum of 144 weeks ]
• Respiratory-related hospitalizations [ Time Frame: maximum 144 weeks ]
• Cardiovascular mortality or morbidity [ Time Frame: maximum of 144 weeks ]
• 6-minute walk distance (6MWD) [ Time Frame: maximum of 144 weeks ]
• Quality of life assessments [ Time Frame: maximum of 144 weeks ]
• Diffusing capacity of the lung for carbon monoxide (DLCO) [ Time Frame: maximum of 144 weeks ]
• Biological response (Fibrin D-dimer) [ Time Frame: maximum of 144 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis
• Official Title: AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (ACE-IPF)
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Idiopathic Pulmonary Fibrosis

Intervention

• Drug: warfarin
  Oral warfarin (1mg or 2.5mg) titrated to an INR of 2-3.
  Other Name: warfarin sodium
• Drug: placebo
  Oral placebo (1mg or 2.5mg)

Study Arms

• Active Comparator: warfarin
  Oral warfarin titrated to an international normalization ratio (INR) of 2-3
  Intervention: Drug: warfarin
• Placebo Comparator: placebo
  Oral placebo (1mg or 2.5mg)
  Intervention: Drug: placebo

Publications *

• Allen RJ, Stockwell A, Oldham JM, Guillen-Guio B, Schwartz DA, Maher TM, Flores C, Noth I, Yaspan BL, Jenkins RG, Wain LV; International IPF Genetics Consortium. Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis. Thorax. 2022 Aug;77(8):829-833. doi: 10.1136/thoraxjnl-2021-218577. Epub 2022 Jun 10.
• Andrade J, Schwarz M, Collard HR, Gentry-Bumpass T, Colby T, Lynch D, Kaner RJ; IPFnet Investigators. The Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet): diagnostic and adjudication processes. Chest. 2015 Oct;148(4):1034-1042. doi: 10.1378/chest.14-2889.
• Durheim MT, Collard HR, Roberts RS, Brown KK, Flaherty KR, King TE Jr, Palmer SM, Raghu G, Snyder LD, Anstrom KJ, Martinez FJ; IPFnet investigators. Association of hospital admission and forced vital capacity endpoints with survival in patients with idiopathic pulmonary fibrosis: analysis of a pooled cohort from three clinical trials. Lancet Respir Med. 2015 May;3(5):388-96. doi: 10.1016/S2213-2600(15)00093-4. Epub 2015 Apr 15.
• Noth I, Anstrom KJ, Calvert SB, de Andrade J, Flaherty KR, Glazer C, Kaner RJ, Olman MA; Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012 Jul 1;186(1):88-95. doi: 10.1164/rccm.201202-0314OC. Epub 2012 May 3.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: December 9, 2011): 145
• Original Estimated Enrollment (submitted: August 10, 2009): 256
• Actual Study Completion Date: July 2011
• Actual Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)

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:

  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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 35 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00957242
• Other Study ID Numbers: Pro00017156; 5U10HL080413-05 ( U.S. NIH Grant/Contract ); 671
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Duke University
• Original Responsible Party: Dr. Kevin Anstrom, PhD, Duke Clinical Research Institute
• Current Study Sponsor: Duke University
• Original Study Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)
• 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

• PRS Account: Duke University
• Verification Date: April 2013