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

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.

Study Overview

• Status: Completed
• Conditions: Idiopathic Pulmonary Fibrosis
• Intervention / Treatment: Drug: Epigallocatechin-3-gallate (EGCG)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • UC San Francisco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 36 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum plasma concentration of EGCG	The maximum plasma concentration [Cmax] following a single dose of EGCG will be determined	0, 2, 4, 12 hours post dose
Plasma exposure of EGCG	Plasma exposure measured as AUC (area under the concentration curve) following a single dose of EGCG will be determined.	0, 2, 4, 12 hours post dose
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of EGCG	The incidence of treatment-emergent Adverse Events [Safety and Tolerability] following EGCG treatment will be assessed.	14 days

Collaborators and Investigators

• Sponsor: Hal Chapman
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Hal A Chapman, MD, UC San Francisco

Publications and helpful links

General Publications

• Chapman HA, Wei Y, Montas G, Leong D, Golden JA, Trinh BN, Wolters PJ, Le Saux CJ, Jones KD, Hills NK, Foster E, Oldham JM, Linderholm AL, Kotak P, Decaris M, Turner S, Song JW. Reversal of TGFbeta1-Driven Profibrotic State in Patients with Pulmonary Fibrosis. N Engl J Med. 2020 Mar 12;382(11):1068-1070. doi: 10.1056/NEJMc1915189. No abstract available.
• Wei Y, Dong W, Jackson J, Ho TC, Le Saux CJ, Brumwell A, Li X, Klesney-Tait J, Cohen ML, Wolters PJ, Chapman HA. Blocking LOXL2 and TGFbeta1 signalling induces collagen I turnover in precision-cut lung slices derived from patients with idiopathic pulmonary fibrosis. Thorax. 2021 Jul;76(7):729-732. doi: 10.1136/thoraxjnl-2020-215745. Epub 2021 Jan 20.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2017
• Primary Completion (Actual): May 31, 2019
• Study Completion (Actual): May 31, 2019

Study Registration Dates

• First Submitted: April 18, 2019
• First Submitted That Met QC Criteria: April 23, 2019
• First Posted (Actual): April 26, 2019

Study Record Updates

• Last Update Posted (Estimate): December 22, 2022
• Last Update Submitted That Met QC Criteria: December 8, 2022
• Last Verified: December 1, 2022

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; Antineoplastic Agents; Neuroprotective Agents; Protective Agents; Antioxidants; Anticarcinogenic Agents; Antimutagenic Agents; Epigallocatechin gallate
• Other Study ID Numbers: 17-23008; R01HL142265 (U.S. NIH Grant/Contract)

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