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

Hal Chapman

Status and phase: Completed; Early Phase 1

Conditions: Idiopathic Pulmonary Fibrosis

Treatments: Drug: Epigallocatechin-3-gallate (EGCG)

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT03928847

R01HL142265 (U.S. NIH Grant/Contract)

17-23008

Details and patient eligibility

About

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.

Full 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.

Enrollment: 35 patients

Sex: All

Ages: 40 to 70 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Other

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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35 participants in 5 patient groups

EGCG PK in healthy volunteers 450 mg

Other group

Description:

Healthy volunteers: 450 mg Epigallocatechin-3-gallate (EGCG) capsules administered once daily by mouth

Treatment:

Drug: Epigallocatechin-3-gallate (EGCG)

EGCG PK in healthy volunteers 600 mg

Other group

Description:

Healthy volunteers: 600 mg Epigallocatechin-3-gallate (EGCG) capsules administered once daily by mouth

Treatment:

Drug: Epigallocatechin-3-gallate (EGCG)

EGCG PK in healthy volunteers 750 mg

Other group

Description:

Healthy volunteers: 750 mg Epigallocatechin-3-gallate (EGCG) capsules administered once daily by mouth

Treatment:

Drug: Epigallocatechin-3-gallate (EGCG)

No treatment control in ILD patients

No Intervention group

Description:

Patients: not treated with EGCG

EGCG treatment in ILD patients

Experimental group

Description:

Patients: 600 mg EGCG capsules once daily by mouth for two weeks

Treatment:

Drug: Epigallocatechin-3-gallate (EGCG)