Safety and Efficacy of a Lysophosphatidic Acid Receptor Antagonist in Idiopathic Pulmonary Fibrosis

Study Overview
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Brief Summary
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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).

Official Title
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Safety and Efficacy of a Lysophosphatidic Acid Receptor Antagonist in Idiopathic Pulmonary Fibrosis

Conditions
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Idiopathic Pulmonary Fibrosis

Intervention / Treatment
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* Drug: BMS-986020
* Drug: Placebo matching with BMS-986020


Participation Criteria
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Eligibility Criteria
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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. Women must have a negative urine pregnancy test within 24 hours prior to the start of investigational product. Women must not be breastfeeding. 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. 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 Has significant clinical worsening of IPF between screening and day 1 (during the screening process), in the opinion of the investigator. Has forced expiratory volume in 1 second (FEV1)/FVC ratio less than 0.8 after administration of bronchodilator at screening. 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 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. 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. 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. Currently has clinically significant asthma or chronic obstructive pulmonary disease. Has clinical evidence of active infection, including, but not limited to, bronchitis, pneumonia, sinusitis, urinary tract infection, and cellulitis. 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). 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. Has a history of end-stage liver disease. Has a history of end-stage renal disease requiring dialysis. 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 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. Has a history of alcohol or substance abuse in the past 2 years. Has a family or personal history of long QT syndrome and/or Torsades de Pointes (polymorphic ventricular tachycardia). 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 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. Has creatinine clearance less than 30 mL/minute, calculated using the Cockcroft-Gault formula. 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 Is not a suitable candidate for enrollment or is unlikely to comply with the requirements of this study, in the opinion of the investigator. Has smoked cigarettes within 4 weeks or screening or is unwilling to avoid tobacco products throughout the study. 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. Prisoners or subjects who are involuntarily incarcerated. Subjects who are compulsorily detained for treatment either of a psychiatric or physical (e.g., infectious disease) illness. Inability to comply with restrictions and prohibited activities/treatments as listed in Section 3.3 of the Protocol.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: BMS 986020, 600 mg. once daily<br>BMS-986020, 600 mg tablets, by mouth, once daily, 26 weeks | Drug: BMS-986020<br> <br> |
| Experimental: Arm 2: BMS-986020, 600 mg twice daily<br>BMS-986020, 600 mg tablets, by mouth, twice daily, 26 weeks | Drug: BMS-986020<br> <br> |
| Placebo Comparator: Arm 3: Placebo matching with BMS-986020<br>Placebo, 0 mg tablets, by mouth, twice daily, 26 weeks | Drug: Placebo matching with BMS-986020<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Forced Vital Capacity (FVC) Rate to Week 26 | FVC is the is the total amount of air exhaled during the forced expiratory volume test that is measured during spirometry; and is the most important measurement of lung function. This test requires participant to breath into a tube connected to a machine that measures the amount of air that can be moved in and out of the lungs after taking an inhaled bronchodilator medicine which is used to dilate participant's bronchial (breathing) tubes. | Baseline, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Ratio (GMR) of Quantitative Lung Fibrosis (QLF) Score at Week 26 to Baseline | The QLF score itself ranges from 0 to 100%, where greater values represent a greater amount of lung fibrosis and are considered a worse health status. Hence smaller geometric mean ratios to baseline were considered favorable. Baseline included all testing done on Day -1 as well as predose on Day 1. | Baseline, Week 26 | 
| Mean Change From Baseline in Six-minute Walk Test (6MWT) Distance to Week 26 | The 6MWT measures the distance (in meters), a participant is able to walk in 6 minutes. This test measures the distance a person can walk quickly on a flat, hard surface in 6 minutes and reflects an individual's ability to perform daily physical activities. Baseline included all testing done on Day -1 as well as predose on Day 1 | Baseline, Week 26 | 
| 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 | The UCSD SOBQ is a 24-item questionnaire developed to measure breathlessness on a scale between zero and five where 0 is not at all breathless and 5 is maximally breathless or too breathless to do the activity. Baseline included all testing done on Day -1 as well as predose on Day 1. The total score ranges from 0 to 120, with higher scores indicating worse dyspnea. | Baseline, Week 26 | 
| Mean Change From Baseline in Forced Vital Capacity (FVC) to Week 26 | FVC is is the total amount of air exhaled during the forced expiratory volume test that is measured during spirometry; and is the most important measurement of lung function. This test requires participant to breath into a tube connected to a machine that measures the amount of air that can be moved in and out of lungs after taking an inhaled bronchodilator medicine which is used to dilate bronchial (breathing) tubes. Baseline included all testing done on Day -1 as well as predose on Day 1 | Baseline, Week 26 | 
| 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 | The SF-36 determines participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 primarily contribute to the Aggregate Physical score of the SF-36. Items 5-8 primarily contribute to the Aggregate mental score of the SF-36. Scores on each item are summed and averaged. Range for Aggregate Physical Score : 0=worst to 100=best; and for Aggregate Mental Score: 0=worst to 100=best. Increases from baseline indicate improvement. Baseline included all testing done on Day -1 as well as predose on Day 1 | Baseline, Week 26 | 
| Number of Participants With Death or Non-Elective Hospitalization | Time to death or non-elective hospitalization was defined as the elapsed time (days) from randomization to the date of death or the first non-elective hospitalization. | Upto Day 210 | 
| 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) | Number of participants with death or respiratory hospitalization or 10% decline in absolute volume of FVC or 25 meter loss in 6MWD over time were reported. | Upto Day 210 | 
| Mean Change From Baseline in Carbon Monoxide Diffusing Capacity (DLCO) to Week 26 | DLCO is a measurement of the ability of the lungs to transfer gases from the air to the blood. Participant breathe in (inhale) air containing a very small, harmless amount of a tracer gas, such as carbon monoxide. Participant hold the breath for 10 seconds, then rapidly blow it out (exhale). The exhaled gas was tested to determine how much of the tracer gas was absorbed during the breath. DLCO, both uncorrected and corrected for hemoglobin in milliliter per minute per millimeter of mercury (mL/min/mmHg) was assessed. | Baseline, Week 26 | 
| Number of Participants With Definite or Probable Acute Exacerbation (AEx) of Idiopathic Pulmonary Fibrosis (IPF) | Acute IPF exacerbations is defined as a clinically significant deterioration of unidentifiable cause in a participant with underlying IPF. Exacerbations of IPF were adjudicated as definite (>=1 AEx) and Probable. Investigators were asked to make the diagnosis of acute exacerbation of IPF on the basis of subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The final diagnosis, however, was confirmed by the study medical monitor. | Upto Day 210 | 
| Maximum Observed Plasma Concentration (Cmax) BMS-986020 | Cmax is defined as the maximum observed plasma concentration. | Day 1 and Day 7 | 
| Time of Maximum Observed Plasma Concentration (Tmax) of BMS-986020 | Tmax is defined as the maximum observed plasma concentration. | Day 1 and Day 7 | 
| Accumulation Index (AI) of BMS-986020 | AI is the ratio of area under the concentration time curve in one dosing interval in (AUC[TAU]) at steady-state to AUC(TAU) after the first dose. | Day 7 | 
| Area Under the Concentration Time Curve in One Dosing Interval of BMS -986020 in at Steady-state | AUC(TAU) is the area under the concentration time curve in one dosing interval in at steady-state. | Day 1 and Day 7 | 
| Area Under the Plasma Concentration-time Curve Over 12 Hours Post-dose AUC(0-12) of BMS -986020 | AUC(0-12) is the area under the plasma concentration time curve over 12 hours post-dose. | Day 1 and Day 7 | 
| Apparent Oral Clearance (CLF/F) of BMS -986020 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Day 1 and Day 7 | 
| Average Concentration of BMS -986020 at Steady State (Css[Avg]) | Css (avg) is the average concentration at steady state. | Day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IPF