Clinical trial NCT03928847: Fibroblast Specific Inhibition of LOXL2 and TGFbeta1 Signaling in Patients With Pulmonary Fibrosis.
Official title: Fibroblast Specific Inhibition of LOXL2 and TGFbeta1 Signaling in Patients With Pulmonary Fibrosis.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Idiopathic Pulmonary Fibrosis
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2019-04-26
Enrollment: 35
Sex: ALL
Minimum age (years): 40
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

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.

Eligibility 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

Primary outcomes:
measure: EGCG PK Level in Healthy Volunteers
timeFrame: 0, 0.5, 2, 4 hours after EGCG
measure: Change of Serum Biomarker COMP Before and After EGCG Treatment in ILD Patients
timeFrame: Day 1 to day 14
measure: Change of Serum Biomarker Periostin Before and After EGCG Treatment in ILD Patients
timeFrame: Day 1 to day 14
measure: Difference of Biomarker Snail1 Between EGCG-treated and Non-treated Patient Groups
timeFrame: 14 days
measure: Difference of Biomarker Collagen I Between EGCG-treated and Non-treated Patient Groups
timeFrame: 14 days
measure: Difference of Biomarker p-Smad3 Between EGCG-treated and Non-treated Patient Groups
timeFrame: 14 days
Secondary outcomes:
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UC San Francisco
state: California
Study officials:
affiliation: UC San Francisco
name: Hal A Chapman, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.