Fibroblast Specific Inhibition of LOXL2 and TGFbeta1 Signaling in Patients With Pulmonary Fibrosis.

Study Overview
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Brief Summary
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This is a two part study. In the first part, the pharmacokinetic profile of Epigallocatechin-3-gallate (EGCG) in normal human volunteers given a single oral dose will be determined to set the dose for the second part of the study. In the second part of this study, lung biopsy fragments and urine samples from patients with interstitial lung disease treated with EGCG will be evaluated in biochemical assays and compared to samples from untreated control patients.

Detailed Description
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This is an interventional study intended to test inhibition of a signaling pathway in vivo in patients with interstitial lung disease, but not intended to affect lung function or disease modifications. Doses of oral Epigallocatechin-3-gallate (EGCG) that achieve plasma levels known to be safe in human volunteers and likely to target fibroblast TGFbeta RI kinase will be established. Disposable fragments of biopsies will be evaluated in biochemical assays including pSmad3 and Snail 1 or assayed to determine lysyl oxidase-like 2 (LOXL2) protein and LOXL2 enzyme activity. Urine collected before and after EGCG exposure will be used to determine whether terminal collagen cross-link breakdown products, termed pyridinoline/deoxypyridinoline (PYD/DPD) are changed from baseline. Blood collected before and after EGCG exposure will be assayed for serum biomarkers.

Official Title
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Fibroblast Specific Inhibition of LOXL2 and TGFbeta1 Signaling in Patients With Pulmonary Fibrosis.

Conditions
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Idiopathic Pulmonary Fibrosis

Intervention / Treatment
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* Drug: Epigallocatechin-3-gallate (EGCG)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1: healthy volunteers Part 2: study will consist of patients presenting to the UCSF interstitial lung disease (ILD) outpatient clinic with imaging indicative of lung fibrosis but of uncertain classification, and who are willing to take EGCG for a minimum of 2 weeks prior to surgery. Exclusion Criteria: co-morbidities affect hepatic function, such as HCV infection, cirrhosis, or using drugs with significant hepatic toxicities

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: EGCG PK in healthy volunteers 450 mg<br>Healthy volunteers: 450 mg Epigallocatechin-3-gallate (EGCG) capsules administered once daily by mouth | Drug: Epigallocatechin-3-gallate (EGCG)<br>* Epigallocatechin-3-gallate (EGCG) capsules<br>* Other names: Teavigo;|
| Other: EGCG PK in healthy volunteers 600 mg<br>Healthy volunteers: 600 mg Epigallocatechin-3-gallate (EGCG) capsules administered once daily by mouth | Drug: Epigallocatechin-3-gallate (EGCG)<br>* Epigallocatechin-3-gallate (EGCG) capsules<br>* Other names: Teavigo;|
| Other: EGCG PK in healthy volunteers 750 mg<br>Healthy volunteers: 750 mg Epigallocatechin-3-gallate (EGCG) capsules administered once daily by mouth | Drug: Epigallocatechin-3-gallate (EGCG)<br>* Epigallocatechin-3-gallate (EGCG) capsules<br>* Other names: Teavigo;|
| No Intervention: No treatment control in ILD patients<br>Patients: not treated with EGCG | |
| Experimental: EGCG treatment in ILD patients<br>Patients: 600 mg EGCG capsules once daily by mouth for two weeks | Drug: Epigallocatechin-3-gallate (EGCG)<br>* Epigallocatechin-3-gallate (EGCG) capsules<br>* Other names: Teavigo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EGCG PK Level in Healthy Volunteers | EGCG plasma levels in healthy volunteers were measured at 0, 0.5, 2, and 4 hours after a single dose at 450 mg, 600 mg, or 750 mg dosage by liquid chromatography-mass spectrometry (LC-MS). | 0, 0.5, 2, 4 hours after EGCG | 
| Change of Serum Biomarker COMP Before and After EGCG Treatment in ILD Patients | Change from baseline to day 14 in serum biomarkers associated with IPF, Cartilage Oligomeric Matrix Protein (COMP) measured by ELISA. | Day 1 to day 14 | 
| Change of Serum Biomarker Periostin Before and After EGCG Treatment in ILD Patients | Change from baseline to day 14 in serum biomarkers associated with IPF, Periostin measured by ELISA. | Day 1 to day 14 | 
| Difference of Biomarker Snail1 Between EGCG-treated and Non-treated Patient Groups | Levels of biomarker Snail1 in lung biopsy tissues 14 days after EGCG were measured by western blot and differences were compared between EGCG-treated and non-treated groups. | 14 days | 
| Difference of Biomarker Collagen I Between EGCG-treated and Non-treated Patient Groups | Levels of biomarker Collagen I in lung biopsy tissues 14 days after EGCG were measured by western blot and differences were compared between EGCG-treated and non-treated groups. | 14 days | 
| Difference of Biomarker p-Smad3 Between EGCG-treated and Non-treated Patient Groups | Levels of biomarker p-Smad3 in lung biopsy tissues 14 days after EGCG were measured by western blot and differences were compared between EGCG-treated and non-treated groups. | 14 days |