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

• ClinicalTrials.gov Identifier: NCT03928847
• Recruitment Status: Recruiting
• First Posted: April 26, 2019
• Last Update Posted: April 26, 2019
• Sponsor: University of California, San Francisco
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): University of California, San Francisco

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Idiopathic Pulmonary Fibrosis	Drug: Epigallocatechin-3-gallate (EGCG)	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 35 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Masking Description: Open Label
• Primary Purpose: Basic Science
• Official Title: Fibroblast Specific Inhibition of LOXL2 and TGFbeta1 Signaling in Patients With Pulmonary Fibrosis.
• Actual Study Start Date: July 1, 2018
• Estimated Primary Completion Date: July 2020
• Estimated Study Completion Date: December 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: EGCG treatment; Healthy volunteers: 450 mg, 600 mg, or 750 mg Epigallocatechin-3-gallate (EGCG) capsules administered once daily by mouth Patients: 600 mg EGCG capsules once daily by mouth for two weeks	Drug: Epigallocatechin-3-gallate (EGCG); Epigallocatechin-3-gallate (EGCG) capsules; Other Name: Teavigo

Outcome Measures

Primary Outcome Measures :

1. Analysis of biomarker levels from Lung tissue specimens [ Time Frame: Day 14 ]
   LOXL2 activity and TGFbeta1 signaling biomarkers such as Snail1 and pSmad3 will be measured in lung tissue from subjects treated with EGCG and compared levels seen in to lung tissue from untreated control subjects.
2. Change from baseline in urinary biomarkers of LOXL2 collagen crosslinking [ Time Frame: Change from day 1 to day 14 ]
   Change from baseline to day 14 in biomarkers representative of LOXL2 collagen crosslinking will be measured in urine samples collected on day 1 and day 14.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 40 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Contacts

Contact: Hal A Chapman, MD; 415-514-1210; Hal.Chapman@ucsf.edu

Locations

United States, California

UC San Francisco; Recruiting

San Francisco, California, United States, 94143

Contact: Hal A Chapman, MD 415-514-1210

Sponsors and Collaborators

University of California, San Francisco

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Hal A Chapman, MD; UC San Francisco

More Information

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT03928847 History of Changes
• Other Study ID Numbers: 17-23008; R01HL142265 ( U.S. NIH Grant/Contract )
• First Posted: April 26, 2019
• Last Update Posted: April 26, 2019
• Last Verified: April 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Idiopathic Interstitial Pneumonias; Fibrosis; Pathologic Processes; Lung Diseases; Respiratory Tract Diseases; Lung Diseases, Interstitial; Epigallocatechin gallate; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs; Antimutagenic Agents; Anticarcinogenic Agents; Antineoplastic Agents; Neuroprotective Agents