Clinical trial NCT01766817: Safety and Efficacy of a Lysophosphatidic Acid Receptor Antagonist in Idiopathic Pulmonary Fibrosis
Official title: Safety and Efficacy of a Lysophosphatidic Acid Receptor Antagonist in Idiopathic Pulmonary Fibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Idiopathic Pulmonary Fibrosis
Keywords: IPF
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2013-01-11
Enrollment: 325
Sex: ALL
Minimum age (years): 40
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine if study drug (BMS-986020) dose of 600 mg once daily or 600 mg twice daily for 26 weeks compared with placebo will reduce the decline in forced vital capacity (FVC) and will be well tolerated in subjects with idiopathic pulmonary fibrosis (IPF).


Eligibility criteria: Inclusion Criteria:

* Are between the ages of 40 and 90 years, inclusive, at randomization.
* Have clinical symptoms consistent with IPF.
* Have first received a diagnosis of IPF less than 6 years before randomization. The date of diagnosis is defined as the date of the first available imaging or surgical lung biopsy consistent with IPF/UIP.
* Have a diagnosis of usual interstitial pulmonary fibrosis (UIP) or IPF by HRCT or surgical lung biopsy (SLB).
* Extent of fibrotic changes (honeycombing, reticular changes) greater than the extent of emphysema on HRCT scan.
* Have no features supporting an alternative diagnosis on transbronchial biopsy, BAL, or SLB, if performed.
* Have percent predicted post-bronchodilator FVC between 45% and 90%, inclusive, at screening.
* Have a change in post-bronchodilator FVC (measured in liters) between screening and day 1 that is less than a 10% relative difference, calculated as: the absolute value of 100% \* (screening FVC (L) - day 1 FVC (L)) / screening FVC (L).
* Have carbon monoxide diffusing capacity (DLCO) between 30% and 80% (adjusted for hemoglobin and altitude), inclusive, at screening.
* Have no evidence of improvement in measures of IPF disease severity over the preceding year, in the investigator's opinion.
* Be able to walk 150 meters or more at screening.
* Demonstrate an exertional decrease in oxygen saturation of 2 percentage points or greater at screening (may be performed with supplemental oxygen titrating to keep oxygen saturation levels \>88%).
* Are able to understand and sign a written informed consent form.
* Are able to understand the importance of adherence to study treatment and the study protocol and are willing to comply with all study requirements, including the concomitant medication restrictions, throughout the study.
* Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP must use acceptable method(s) of contraception. The individual methods of contraception and duration should be determined in consultation with the investigator. WOCBP must follow instructions for birth control when the half-life of the investigational drug is less than 24 hours, contraception should be continued for a period of 30 days after the last dose of investigational product.

  1. Women must have a negative urine pregnancy test within 24 hours prior to the start of investigational product.
  2. Women must not be breastfeeding.
  3. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men that are sexually active with WOCBP must follow instructions for birth control when the half-life of the investigational drug is less than 24 hours, contraception should be continued for a period of 90 days after the last dose of investigational product.
  4. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and azoospermic men do not require contraception.

Exclusion Criteria:

Target Disease Exclusions

1. Has significant clinical worsening of IPF between screening and day 1 (during the screening process), in the opinion of the investigator.
2. Has forced expiratory volume in 1 second (FEV1)/FVC ratio less than 0.8 after administration of bronchodilator at screening.
3. Has bronchodilator response, defined by an absolute increase of 12% or greater and an increase of 200 mL in FEV1 or FVC or both after bronchodilator use compared with the values before bronchodilator use at screening.

Medical History and Concurrent Diseases

1. Has a history of clinically significant environmental exposure known to cause pulmonary fibrosis, including, but not limited to, drugs (such as amiodarone), asbestos, beryllium, radiation, and domestic birds.
2. Has a known explanation for interstitial lung disease, including, but not limited to, radiation, drug toxicity, sarcoidosis, hypersensitivity, pneumonitis, bronchiolitis, obliterans, organizing pneumonia, human immunodeficiency virus (HIV), viral hepatitis, and cancer.
3. Has a clinical diagnosis of any connective tissue disease, including, but not limited to, scleroderma, polymyositis/dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, and undifferentiated connective tissue disease.
4. Currently has clinically significant asthma or chronic obstructive pulmonary disease.
5. Has clinical evidence of active infection, including, but not limited to, bronchitis, pneumonia, sinusitis, urinary tract infection, and cellulitis.
6. Has any history of malignancy likely to result in significant disability or likely to require significant medical or surgical intervention within the next 2 years. This does not include minor surgical procedures for localized cancer (e.g., basal cell carcinoma).
7. Has any condition other than IPF that, in the opinion of the investigator, is likely to result in the death of the subject within the next 2 years.
8. Has a history of end-stage liver disease.
9. Has a history of end-stage renal disease requiring dialysis.
10. Has a history of unstable or deteriorating cardiac or pulmonary disease (other than IPF) within the previous 6 months, including, but not limited to, the following: i. Unstable angina pectoris or myocardial infarction ii. Congestive heart failure requiring hospitalization iii. Uncontrolled clinically significant arrhythmias
11. Has any condition that, in the opinion of the investigator, might be significantly exacerbated by the known side effects associated with the administration of BMS-986020.
12. Has a history of alcohol or substance abuse in the past 2 years.
13. Has a family or personal history of long QT syndrome and/or Torsades de Pointes (polymorphic ventricular tachycardia).
14. Has used any of the excluded medications per Appendix 1 of the Protocol, which includes, but is not limited to:

    * current treatment with pirfenidone or nintedanib
    * use of over-the-counter medications and herbal preparations, within 4 weeks before study drug administration except those medications cleared by the BMS medical monitor
    * For subjects taking statins, there are restrictions on the maximum allowable doses for statins listed below. If subjects are currently taking statins and their doses are higher than those mentioned below, please reduce the dose to the maximum allowable dose.

Additionally, if subjects are on statins and ready to start dosing, these subjects should limit statin doses by maximal allowable dose or lower for at least 5 days prior to the first BMS-986020 dosing. Shorter durations may be considered in select cases after discussion with the medical monitor.

Maximum allowable dose for statins:

* Simvastatin 20 mg QD
* Pitavastatin 2 mg QD
* Atorvastatin 40 mg QD
* Pravastatin 40 mg QD
* Rosuvastatin 20 mg QD
* Lovastatin 40 mg QD
* Fluvastatin 40 mg QD
* Prednisone is allowed up to a maximum of 15 mg po daily
* Pirfenidone or nintedanib dosing for a maximum of 3 months in the prior 12 months is permitted with a 4 week washout period prior to dosing with BMS-986020.

Physical and Laboratory Test Findings

1. Has any of the following liver-function test criteria above the specified limits: total bilirubin \>1.5 x ULN, excluding subjects with Gilbert's syndrome; aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) greater than 3 x ULN; alkaline phosphatase greater than 2.5 x ULN.
2. Has creatinine clearance less than 30 mL/minute, calculated using the Cockcroft-Gault formula.
3. Has ECG result with a QT interval by Fridericia's correction (QTcF) of 500 msec or greater or an uncorrected QT of 500 msec or greater at screening. Note: For subjects with a machine read QT interval of \>500 msec, if their heart rate is \> 100 bpm, the machine read QT interval (either corrected or not) may not be accurate. If the investigator is uncertain about the QT abnormality, it is recommended that ECGs be over-read by a cardiologist. The manually read QT interval by a cardiologist should be used for assessment of eligibility whenever possible.

Allergies and Adverse Drug Reaction Has had prior use of BMS-986020 or has known hypersensitivity to any of the components of study treatment.

Other Exclusion Criteria

1. Is not a suitable candidate for enrollment or is unlikely to comply with the requirements of this study, in the opinion of the investigator.
2. Has smoked cigarettes within 4 weeks or screening or is unwilling to avoid tobacco products throughout the study.
3. Is expected to receive a lung transplant within 1 year from randomization or, for subjects at sites in the United States, is on a lung-transplant waiting list at screening.
4. Prisoners or subjects who are involuntarily incarcerated.
5. Subjects who are compulsorily detained for treatment either of a psychiatric or physical (e.g., infectious disease) illness.
6. Inability to comply with restrictions and prohibited activities/treatments as listed in Section 3.3 of the Protocol.

Primary outcomes:
measure: Change From Baseline in Forced Vital Capacity (FVC) Rate to Week 26
timeFrame: Baseline, Week 26
Secondary outcomes:
measure: Geometric Mean Ratio (GMR) of Quantitative Lung Fibrosis (QLF) Score at Week 26 to Baseline
timeFrame: Baseline, Week 26
measure: Mean Change From Baseline in Six-minute Walk Test (6MWT) Distance to Week 26
timeFrame: Baseline, Week 26
measure: Mean Change From Baseline in the University of California at San Diego Shortness of Breath Questionnaire (UCSD SOBQ) Total Score as a Measure of Dyspnea to Week 26
timeFrame: Baseline, Week 26
measure: Mean Change From Baseline in Forced Vital Capacity (FVC) to Week 26
timeFrame: Baseline, Week 26
measure: Mean Change From Baseline in Quality of Life as Measured by the Medical Outcomes Study (MOS) 36-Item Short-Form Health Survey (SF-36) to Week 26
timeFrame: Baseline, Week 26
measure: Number of Participants With Death or Non-Elective Hospitalization
timeFrame: Upto Day 210
measure: Number of Participants With Death or Respiratory Hospitalization or 10 Percent (%) Decline in Absolute Volume of FVC or 25-Meter Loss in 6-Minute Walk Distance (6MWD)
timeFrame: Upto Day 210
measure: Mean Change From Baseline in Carbon Monoxide Diffusing Capacity (DLCO) to Week 26
timeFrame: Baseline, Week 26
measure: Number of Participants With Definite or Probable Acute Exacerbation (AEx) of Idiopathic Pulmonary Fibrosis (IPF)
timeFrame: Upto Day 210
measure: Maximum Observed Plasma Concentration (Cmax) BMS-986020
timeFrame: Day 1 and Day 7
measure: Time of Maximum Observed Plasma Concentration (Tmax) of BMS-986020
timeFrame: Day 1 and Day 7
measure: Accumulation Index (AI) of BMS-986020
timeFrame: Day 7
measure: Area Under the Concentration Time Curve in One Dosing Interval of BMS -986020 in at Steady-state
timeFrame: Day 1 and Day 7
measure: Area Under the Plasma Concentration-time Curve Over 12 Hours Post-dose AUC(0-12) of BMS -986020
timeFrame: Day 1 and Day 7
measure: Apparent Oral Clearance (CLF/F) of BMS -986020
timeFrame: Day 1 and Day 7
measure: Average Concentration of BMS -986020 at Steady State (Css[Avg])
timeFrame: Day 7
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham - Division of Pulmonary, Allergy & Criticial Care
state: Alabama
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center - Heart Lung Institute/ Clinical Research
state: Arizona
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA
state: California
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine, Section of Pulmonary & Critical Care
state: Connecticut
city: Daytona Beach
country: United States
facility: Advanced Pulmonary & Sleep Research Institute of Florida
state: Florida
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: ILD Research Center
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic Florida- Weston Hospital
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Wichita
country: United States
facility: Via Christi Clinic
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky- Center for Clinical and Translational Science
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic, Pulmonary Clinical Research Unit
state: Minnesota
city: Chesterfield
country: United States
facility: CardioPulmonary Research Center
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Summit
country: United States
facility: Pulmonary & Allergy Associates, PA
state: New Jersey
city: Forest Hills
country: United States
facility: ISA Clinical Research
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Rochester
country: United States
facility: Highland Hospital
state: New York
city: Asheville
country: United States
facility: Asheville Pulmonary and Critical Care Associates, P.A.
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Pulmonary, Critical Care & Sleep Medicine
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Portland
country: United States
facility: The Oregon Clinic
state: Oregon
city: Portland
country: United States
facility: Oregon Health Science University
state: Oregon
city: Philadelphia
country: United States
facility: Temple Lung Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center - Simmons Center for Interstitial Lung Disease
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center - Dallas
state: Texas
city: McKinney
country: United States
facility: Metroplex Pulmonary and Sleep Center
state: Texas
city: San Antonio
country: United States
facility: Alamo Clinical Research
state: Texas
city: Tyler
country: United States
facility: University of Texas Health Science Center at Tyler
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Colchester
country: United States
facility: Vermont Lung Center
state: Vermont
city: Falls Church
country: United States
facility: Inova Fairfax Medical Campus
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin Hospital & Clinics
state: Wisconsin
city: Westmead
country: Australia
facility: Local institution
state: New South Wales
city: Greenslopes
country: Australia
facility: Local institution
state: Queensland
city: Adelaide
country: Australia
facility: Local Institution
state: South Australia
city: Frankston
country: Australia
facility: Local institution
state: Victoria
city: Nedlands
country: Australia
facility: Local institution
state: Western Australia
city: Vina Del Mar
country: Chile
facility: Local institution
state: Valparaiso
city: Quillota
country: Chile
facility: Local institution
city: Santiago
country: Chile
facility: Local institution
city: Talca
country: Chile
facility: Local Institution
city: Medellin
country: Colombia
facility: Hospital Pablo Tobon Uribe
state: Antioquia
city: Bogota
country: Colombia
facility: Fundacion Neumologica Colombiana
state: Cundinamarca
city: Bogota
country: Colombia
facility: Hospital Universitario San Ignacio
state: Cundinamarca
city: Bogota
country: Colombia
facility: Local Institution
state: Cundinamarca
city: Mexico City
country: Mexico
facility: Local Institution
state: Distrito Federal
city: Mexico City
country: Mexico
facility: Local Institution
state: Distrito Federal
city: Guadalajara
country: Mexico
facility: Local Institution
state: Jalisco
city: Monterrey
country: Mexico
facility: Local Institution
state: Nuevo Leon
city: Monterrey
country: Mexico
facility: Local Institution
state: Nuevo Leon
city: Monterrey
country: Mexico
facility: Local Institution
state: Nuevo Leon
city: Lima
country: Peru
facility: Local institution
city: Lima
country: Peru
facility: Local Institution
city: Lima
country: Peru
facility: Local institution
city: Lima
country: Peru
facility: Local institution
city: Lima
country: Peru
facility: Local institution
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Decato BE, Leeming DJ, Sand JMB, Fischer A, Du S, Palmer SM, Karsdal M, Luo Y, Minnich A. LPA1 antagonist BMS-986020 changes collagen dynamics and exerts antifibrotic effects in vitro and in patients with idiopathic pulmonary fibrosis. Respir Res. 2022 Mar 18;23(1):61. doi: 10.1186/s12931-022-01980-4.
citation: Palmer SM, Snyder L, Todd JL, Soule B, Christian R, Anstrom K, Luo Y, Gagnon R, Rosen G. Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial of BMS-986020, a Lysophosphatidic Acid Receptor Antagonist for the Treatment of Idiopathic Pulmonary Fibrosis. Chest. 2018 Nov;154(5):1061-1069. doi: 10.1016/j.chest.2018.08.1058. Epub 2018 Sep 7.