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

Idiopathic Pulmonary Fibrosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03928847
• Other study ID #: 17-23008
• Secondary ID: R01HL142265
• Status: Completed
• Phase: Early Phase 1
• Start date: December 1, 2017
• Est. completion date: May 31, 2019

Study information

• Verified date: December 2022
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: May 31, 2019
• Est. primary completion date: May 31, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 40 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Fibrosis
• Idiopathic Pulmonary Fibrosis
• Pulmonary Fibrosis

Intervention

Drug:
• Epigallocatechin-3-gallate (EGCG)
Epigallocatechin-3-gallate (EGCG) capsules

Locations

Country	Name	City	State
United States	UC San Francisco	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
Hal Chapman	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (2)

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 Fibr — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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