BMS IM136003

Overview

Status: Recruiting
Keywords: IPF , Idiopathic Pulmonary Fibrosis , Pulmonary Disease
IRB Number: 00061976
Specialty: Pulmonary, Pulmonary, Pulmonary, Pulmonary
Sub Specialties: Pulmonary Fibrosis, Pulmonary Function, General Pulmonary, Pulmonary

Brief Summary

 

 

This study, is being conducted to assess the safety and efficacy of BMS-986020 on the management of patients with IPF. Lysophosphatidic acid receptor 1 (LPA1) has been implicated in the development of IPF, and BMS-986020 is a high-affinity, selective, small-molecule antagonist of LPA1 being developed as a chronic oral treatment for lung fibrosis associated with systemic sclerosis and IPF.

 

The primary objective of this study is to compare the rate of change in FVC (liters) from baseline to 26 weeks in subjects with IPF randomized to BMS-986020 600 mg once daily or BMS-986020 600 mg twice daily, vs. placebo.

The secondary objective is to evaluate the safety of treatment with BMS-986020 compared with placebo in subjects with IPF. Secondary efficacy objectives are to assess the effect of treatment with BMS-986020 on change in walk distance and dyspnea in patients with IPF. Additional secondary objectives are:

Estimate the systemic exposure of BMS-986020 in subjects with IPF following single- and multiple-dose administration

Mean change in 6MWT distance from baseline to week 26 Mean change in dyspnea from baseline to week 26 as measured by the University of

California at San Diego Shortness of Breath Questionnaire (UCSD SOBQ)

Mean change in FVC (liters) from baseline to week 26

Mean change in quality of life from baseline to week 26 as measured by the SF-36®

Time to death or non-elective hospitalization

Time to death or respiratory hospitalization or 10% decline in absolute volume of FVC or 25-meter loss in 6-minute walk distance (6MWD)

Mean change in DLCO from baseline to week 26 Acute exacerbation of IPF

 

Exploratory Objectives:

Number of all-cause hospitalizations

Number of respiratory hospitalizations

All-cause mortality

Treatment-emergent IPF-related mortality

Time to progression-free survival

Characterize the pharmacokinetics (PK) of BMS-986020 using population PK analysis

Evaluate the relationship between measures of exposure and change in baseline for FVC

Evaluate the relationship between measures of exposure and biomarkers in blood and bronchioalveolar lavage (BAL)

Evaluate the presence or absence of variants in genes associated with pulmonary fibrosis in the study population.

Estimate concentrations of BMS-986020 in BAL fluid Evaluate the change in lung fibrosis extent by high-resolution computed tomography

(HRCT)

Evaluate the change in regional lung perfusion, ventilation, and diffusion by-contrast- enhanced MRI and HPG-MRI

Principal Investigator: Mary Scholand
Department: Pulmonary
Co Investigator:

Contact Information

Name:Spencer Whipple
Phone: 801-581-5811
Email: spencer.whipple@hsc.utah.edu

Inclusion Criteria

 

Inclusion Criteria

For entry into the study, the following criteria MUST be met before dosing on day 1. No exceptions will be granted.

1) Are between the ages of 40 and 80 years, inclusive, at randomization.

2) Have clinical symptoms consistent with IPF before screening

3) Have first received a diagnosis of IPF at least 6 months and no more than 48 months before randomization.

4) Have a diagnosis of usual interstitial pulmonary fibrosis (UIP) or IPF by high- resolution computed tomography (HRCT) or surgical lung biopsy (SLB)

 

5) Extent of fibrotic changes (honeycombing, reticular changes) greater than the extent of emphysema on HRCT scan.

6) Have no features supporting an alternative diagnosis on transbronchial biopsy, BAL, or SLB, if performed.

7) Have percent predicted post-bronchodilator FVC between 50% and 80%, inclusive, at screening.

8) 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).

9)Have carbon monoxide diffusing capacity (DLCO) between 30% and 80%, inclusive, at screening.

10) Have no evidence of improvement in measures of IPF disease severity over the preceding year, in the investigator's opinion.

11) Be able to walk 150 meters or more during the 6MWT at screening.

12)Demonstrate a decrease in oxygen saturation of 2 percentage points or greater during the 6MWT at screening (performed without supplemental oxygen unless oxygen saturation is below 88% at initiation of test).

13) Are able to understand and sign a written informed consent form.

14) 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.

15) Women of childbearing potential (WOCBP) must use method(s) of contraception based on the tables in Appendix 2. For a teratogenic study drug and/or when there is insufficient information to assess teratogenicity (preclinical studies have not been done), a highly effective method(s) of contraception (failure rate of less than 1% per year) is required. 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.

a) Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product.

b) Women must not be breastfeeding.

c) Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. The investigator shall review contraception methods and the time period that contraception must be followed. 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.

d) Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile; see Section 3.2.3 for the definition of WOCBP) and azoospermic men do not require contraception

Exclusion Criteria

 

Exclusion Criteria

1) Target Disease Exclusions

a) Has significant clinical worsening of IPF between screening and day 1 (during the screening process), in the opinion of the investigator.

b) Has forced expiratory volume in 1 second (FEV1)/FVC ratio less than 0.8 after administration of bronchodilator at screening.

c) 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.

2) Medical History and Concurrent Diseases

a) 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.

b) 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.

c) 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.

d) Currently has clinically significant asthma or chronic obstructive pulmonary disease.

e) Has clinical evidence of active infection, including, but not limited to, bronchitis, pneumonia, sinusitis, urinary tract infection, and cellulitis.

f) 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).

g) 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.

h) Has a history of end-stage liver disease.

i) Has a history of end-stage renal disease requiring dialysis.

j) 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. ii. iii.

Unstable angina pectoris or myocardial infarction Congestive heart failure requiring hospitalization Uncontrolled clinically significant arrhythmias

k) 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.

l) Has a history of alcohol or substance abuse in the past 2 years.

m) Has a family or personal history of long QT syndrome and/or Torsades de Pointes (polymorphic ventricular tachycardia).

n) Has used of any of the following therapies within 7 days before screening:

i. Investigational therapy, defined as any drug that has not been approved for marketing for any indication in the country of the participating site

ii. Any cytotoxic, immunosuppressive, cytokine-modulating, or receptor-antagonist agent, including, but not limited to, azathioprine, bosentan, ambrisentan, cyclophosphamide, cyclosporine, etanercept, iloprost, infliximab, leukotriene antagonists, methotrexate, mycophenolate mofetil, tacrolimus, montelukast, tetrathiomolybdate, tumor necrosis factor alpha inhibitors, NAC, imatinib mesylate, interferon gamma-1b, pirfenidone, and tyrosine kinase inhibitors.

iii. Angiotensin converting enzyme inhibitors, colchicine, corticosteroids, heparin, and warfarin. Sildenafil (daily use) may be used if given for a non-IPF indication if there is no clinically acceptable alternate therapy for the same indication; intermittent use for erectile dysfunction is allowed.

iv. Intermittent use of corticosteroids is allowed for actute respiratory worsening.

v. Ketoconazole, cyclosporine and steroids for topical and ophthalmic use is permitted.

 

3) Physical and Laboratory Test Findings

a) Has any of the following liver-function test criteria above specified limits: total bilirubin >1.5 ULN, excluding subjects with Gilbert's syndrome; aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) greater than 3 × ULN; alkaline phosphatase greater than 2.5 × ULN.

b) Has creatinine clearance less than 30 mL/minute, calculated using the Cockcroft-Gault formula.

c) Has ECG result with a QT interval by Fridericia’s correction (QTcF) of 450 msec or greater or an uncorrected QT of 500 msec or greater at screening.

4) Allergies and Adverse Drug Reaction

Has had prior use of BMS-986020 or has known hypersensitivity to any of the components of study treatment.

5) Other Exclusion Criteria

a) Is not a suitable candidate for enrollment or is unlikely to comply with the requirements of this study, in the opinion of the investigator.

b) Has smoked cigarettes within 3 months of screening or is unwilling to avoid tobacco products throughout the study.

c) 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.

d) Prisoners or subjects who are involuntarily incarcerated.

e) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.

f) Inability to comply with restrictions and prohibited activities/treatments