Targeting Pro-Inflammatory Cells in Idiopathic Pulmonary Fibrosis: a Human Trial (IPF)

Targeted Removal of Pro-Inflammatory Cells: An Open Label Human Pilot Study in Idiopathic Pulmonary Fibrosis

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.

Study Overview

• Status: Completed
• Conditions: Idiopathic Pulmonary Fibrosis (IPF)
• Intervention / Treatment: Drug: Placebo; Drug: Dasatinib + Quercetin

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health
  • Texas
    • San Antonio, Texas, United States, 78245
      • University of Texas Health Science Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 48 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo
Experimental: Dasatinib + Quercetin	Drug: Dasatinib + Quercetin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of pro-inflammatory expressing cells	A skin biopsy will be obtained at baseline and the percentage of pro-inflammatory expressing cells will be recorded	baseline
Percentage of pro-inflammatory expressing cells	A skin biopsy will be obtained at 4 weeks post baseline/5 days after the last dose of study medication and the percentage of pro-inflammatory expressing cells will be recorded	4 weeks post baseline visit biopsy/ 5 days post last dose study drug
Blood Pressure		screening 1 week pre baseline visit
Blood Pressure		baseline visit
Blood Pressure		4 weeks post baseline
Weight		screening 1 week pre baseline visit
Weight		baseline visit
Weight		4 weeks post baseline
Heart Rate		screening 1 week pre baseline visit
Heart Rate		baseline visit
Heart Rate		4 weeks post baseline
CBC (complete blood count)		screening 1 week pre baseline visit
CBC (complete blood count)		4 weeks post baseline
Lipid Panel		screening 1 week pre baseline visit
Lipid Panel		4 weeks post baseline
HbA1c (glycated hemoglobin)		screening 1 week pre baseline visit
HbA1c (glycated hemoglobin)		4 weeks post baseline
CMP (comprehensive metabolic panel)		screening 1 week pre baseline visit
CMP (comprehensive metabolic panel)		4 weeks post baseline
Plasma hsCRP (high-sensitivity C-reactive protein)		screening 1 week pre baseline visit
Plasma hsCRP (high-sensitivity C-reactive protein)		4 weeks post baseline
Plasma IL-6 (inflammatory biomarker)		baseline
Plasma IL-6 (inflammatory biomarker)		4 weeks post baseline
Plasma IL-6R (inflammatory biomarker)		baseline
Plasma IL-6R (inflammatory biomarker)		4 weeks post baseline
Plasma PASP biomarkers (inflammatory biomarkers)		baseline
Plasma PASP biomarkers (inflammatory biomarkers)		4 weeks post baseline
p16INK4a biomarker (inflammatory biomarker)		baseline
p16INK4a biomarker (inflammatory biomarker)		4 weeks post baseline

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: Mayo Clinic; The University of Texas Health Science Center at San Antonio
• Investigators: Principal Investigator: Stephen Kritchevsky, PhD, Wake Forest Univerisity Health Sciences

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2016
• Primary Completion (Actual): June 3, 2019
• Study Completion (Actual): June 3, 2019

Study Registration Dates

• First Submitted: August 17, 2016
• First Submitted That Met QC Criteria: August 19, 2016
• First Posted (Estimate): August 22, 2016

Study Record Updates

• Last Update Posted (Actual): May 12, 2020
• Last Update Submitted That Met QC Criteria: May 8, 2020
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Fibrosis; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protective Agents; Protein Kinase Inhibitors; Antioxidants; Dasatinib; Quercetin
• Other Study ID Numbers: IRB00037000

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No