Clinical trial NCT00957242: AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis
Official title: AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (ACE-IPF)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Idiopathic Pulmonary Fibrosis
Keywords: IPF
Warfarin
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Duke Clinical Research Institute
First posted: 2009-08-12
Enrollment: 145
Sex: ALL
Minimum age (years): 35
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Death, Non-bleeding/Non-elective Hospitalization, or >10% Drop in Forced Vital Capacity
timeFrame: Events up to 48 weeks
Secondary outcomes:
measure: All Cause Mortality
timeFrame: maximum of 48 weeks
measure: Change in Forced Vital Capacity (FVC) From Baseline to 16 Weeks
timeFrame: 16 weeks
measure: All-cause Hospitalizations
timeFrame: maximum 48 weeks
measure: Bleeding Events
timeFrame: maximum of 48 weeks
measure: Acute Exacerbations of Idiopathic Pulmonary Fibrosis (IPF)
timeFrame: maximum of 48 weeks
measure: Respiratory-related Hospitalizations
timeFrame: maximum 48 weeks
measure: Cardiovascular Mortality or Morbidity
timeFrame: maximum of 48 weeks
measure: Change in 6-minute Walk Distance (6MWD)
timeFrame: Change from baseline to last visit (maximum of 48 weeks)
measure: Total Score St. George's Respiratory Questionnaire (SGRQ)
timeFrame: Week 16 Change from Baseline
measure: Change in Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) From Baseline to 16 Weeks
timeFrame: Week 48 / Final Visit
measure: Fibrin D-dimer Change From Baseline to 16 Weeks
timeFrame: maximum of 48 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: University of California - Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California - San Francisco
state: California
city: Denver
country: United States
facility: National Jewish Medical and Research Center
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Chesterfield
country: United States
facility: St. Luke's Hospital
state: Missouri
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Rochester
country: United States
facility: Highland Hospital - University of Rochester Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health Research Center
state: Utah
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: University of Michigan
name: Galen Toews, MD
role: STUDY_CHAIR
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
name: Gail Weinmann, MD
role: STUDY_DIRECTOR
affiliation: National Jewish Health
name: Kevin Brown, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Weill Medical College at Cornell University
name: Rob Kaner, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Talmadge King, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Tulane University School of Medicine
name: Joe Lasky, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University
name: James Loyd, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Michigan
name: Fernando Martinez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Chicago
name: Imre Noth, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington
name: Ganesh Raghu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Jesse Roman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic
name: Jay Ryu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: Joseph Lynch, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: Kevin Anstrom, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Joao deAndrade, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Cleveland Clinic
name: Jeffrey Chapman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: Lake Morrison, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Highland Hospital
name: Michael Kallay, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of South Carolina
name: Steven Sahn, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Miami
name: Marilyn Glassberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Milton Rossman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas
name: John Fitzgerald, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Utah
name: Mary Beth Scholand, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Luke's Hospital
name: Neil Ettinger, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale University
name: Danielle Antin-Ozerkis, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.