Clinical trial NCT02874989: Targeting Pro-Inflammatory Cells in Idiopathic Pulmonary Fibrosis: a Human Trial
Official title: Targeted Removal of Pro-Inflammatory Cells: An Open Label Human Pilot Study in Idiopathic Pulmonary Fibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Idiopathic Pulmonary Fibrosis (IPF)
Lead sponsor: Wake Forest University Health Sciences
Sponsor class: OTHER
Collaborators: name: Mayo Clinic
name: The University of Texas Health Science Center at San Antonio
First posted: 2016-08-22
Enrollment: 26
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The study team hypothesizes that intermittent (3 doses administered over 3 consecutive days in 3 consecutive weeks) oral administration of combination Dasatinib (100 mg/d) + Quercetin (1250 mg/d) will be safe and well tolerated in patients with IPF. Treatment with D+Q will result in reduced abundance of pro-inflammatory cells within subjects over baseline. Finally, the reduction in biomarkers of cellular pro-inflammatory state will be related to no change in functional and patient reported outcomes.


Eligibility criteria: Inclusion Criteria:

1. Men between ages 50 and above, at the time of signing the informed consent.
2. Post-menopausal women ages 50 and above, at the time of signing the informed consent. Note: Postmenopausal is defined as 12 months of spontaneous amenorrhea determined by self-report.
3. A clinical diagnosis of IPF and characteristic chest HRCT scan (determined by panel of pulmonary radiologists) OR biopsy showing usual interstitial pneumonia (UIP).
4. Body Mass Index (BMI) within the range 19 - 39.9 kg/ m2 (inclusive), where BMI = (weight in kg) / (height in meters)2 .
5. Subjects participating in an exercise program must be willing to maintain their current activity level for the duration of the study period.
6. Patients on stable therapy with nintedanib (Ofev) or pirfenidone (Esbriet) over the past 3 months.ORPatients not taking nintedanib (Ofev) or pirfenidone (Esbriet) may be enrolled if they have previously not tolerated one of those medications or if those medications have not yet been prescribed or used by the patient.
7. Giving signed informed consent.
8. No plans to travel over the next 6 weeks.

Exclusion Criteria:

1. More than two moderate/severe IPF exacerbations within the past year Exacerbation is defined as worsening of two or more of the following major symptoms: dyspnea, sputum volume, sputum purulence OR worsening of any one major symptom together with at least one of the following additional symptoms: sore throat, colds (nasal discharge and/or nasal congestion), fever \> 37.5 ° C without any explained cause, increased cough, increase wheeze.

   A moderate exacerbation is defined as an event that is associated with a new prescription for antibiotics and/or oral steroids. A severe exacerbation is defined as an event that is associated with hospitalization or emergency room visit.
2. Any moderate/severe IPF exacerbation within the past 4 weeks.
3. History of a lung transplant.
4. Use of anti-arrhythmic medications known to cause QTc prolongation.
5. Pulmonary hypertension or cor pulmonale confirmed by echocardiography or heart catheterization.
6. Myocardial infarction, angina, hospitalization for cardiac aetiology, stroke or transient ischemic attack in the past 6 months.
7. Chronic heart failure.
8. Neurologic, musculoskeletal, or other condition that in the opinion of the study physician limits subject's ability to complete study physical assessments.
9. Uncontrolled diabetes (HbA1c \> 8% and fasting glucose \>200 mg/dL or the current use of insulin).
10. Subjects with values outside the specified ranges for the following Key Clinical Laboratory Tests must be excluded from the study:

    Renal function: Glomerular Filtration Rate (GFR) \<30 (mL/min/1.73 m2) using formulae provided in the Study Reference Manual (SRM). Note: Subjects receiving dialysis are excluded from this study.

    ALT \>2xULN and bilirubin \>1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
11. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
12. QTcB or QTcF \> 450 msec or QTc \> 480 msec in subjects with Bundle Branch Block based on a single ECG.
13. Subjects with a history of malignancy that is not in complete remission for at least 2 years or 1 year for non-melanoma skin carcinoma.
14. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to participation in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
15. History of drug or alcohol abuse within 5 years prior to randomization.
16. Use of Coumadin or other anti-platelet or anti-coagulant medication. The use of aspirin is permitted.
17. Current use of quinolone antibiotics.
18. Low CBC.
19. Cognitive Impairment (MoCA score less than 21)
20. Other medical or behavioral factors that in the judgment of the principal investigator may interfere with study participation or the ability to follow the intervention

Primary outcomes:
measure: Percentage of pro-inflammatory expressing cells
timeFrame: baseline
measure: Percentage of pro-inflammatory expressing cells
timeFrame: 4 weeks post baseline visit biopsy/ 5 days post last dose study drug
measure: Blood Pressure
timeFrame: screening 1 week pre baseline visit
measure: Blood Pressure
timeFrame: baseline visit
measure: Blood Pressure
timeFrame: 4 weeks post baseline
measure: Weight
timeFrame: screening 1 week pre baseline visit
measure: Weight
timeFrame: baseline visit
measure: Weight
timeFrame: 4 weeks post baseline
measure: Heart Rate
timeFrame: screening 1 week pre baseline visit
measure: Heart Rate
timeFrame: baseline visit
measure: Heart Rate
timeFrame: 4 weeks post baseline
measure: CBC (complete blood count)
timeFrame: screening 1 week pre baseline visit
measure: CBC (complete blood count)
timeFrame: 4 weeks post baseline
measure: Lipid Panel
timeFrame: screening 1 week pre baseline visit
measure: Lipid Panel
timeFrame: 4 weeks post baseline
measure: HbA1c (glycated hemoglobin)
timeFrame: screening 1 week pre baseline visit
measure: HbA1c (glycated hemoglobin)
timeFrame: 4 weeks post baseline
measure: CMP (comprehensive metabolic panel)
timeFrame: screening 1 week pre baseline visit
measure: CMP (comprehensive metabolic panel)
timeFrame: 4 weeks post baseline
measure: Plasma hsCRP (high-sensitivity C-reactive protein)
timeFrame: screening 1 week pre baseline visit
measure: Plasma hsCRP (high-sensitivity C-reactive protein)
timeFrame: 4 weeks post baseline
measure: Plasma IL-6 (inflammatory biomarker)
timeFrame: baseline
measure: Plasma IL-6 (inflammatory biomarker)
timeFrame: 4 weeks post baseline
measure: Plasma IL-6R (inflammatory biomarker)
timeFrame: baseline
measure: Plasma IL-6R (inflammatory biomarker)
timeFrame: 4 weeks post baseline
measure: Plasma PASP biomarkers (inflammatory biomarkers)
timeFrame: baseline
measure: Plasma PASP biomarkers (inflammatory biomarkers)
timeFrame: 4 weeks post baseline
measure: p16INK4a biomarker (inflammatory biomarker)
timeFrame: baseline
measure: p16INK4a biomarker (inflammatory biomarker)
timeFrame: 4 weeks post baseline
Secondary outcomes:
Other outcomes:
Locations:
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: San Antonio
country: United States
facility: University of Texas Health Science Center
state: Texas
Study officials:
affiliation: Wake Forest Univerisity Health Sciences
name: Stephen Kritchevsky, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, Prata L, Masternak MM, Kritchevsky SB, Musi N, Kirkland JL. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019 Feb;40:554-563. doi: 10.1016/j.ebiom.2018.12.052. Epub 2019 Jan 5.