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

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ClinicalTrials.gov Identifier: NCT03928847
Recruitment Status : Recruiting
First Posted : April 26, 2019
Last Update Posted : January 13, 2021
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE April 18, 2019
First Posted Date  ICMJE April 26, 2019
Last Update Posted Date January 13, 2021
Actual Study Start Date  ICMJE July 1, 2018
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 6, 2020)
  • 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.
  • 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.
  • Analysis of serum biomarker Periostin and COMP levels from blood specimens [ Time Frame: Change from day 1 to day 14 ]
    Change from baseline to day 14 in serum biomarkers associated with IPF
Original Primary Outcome Measures  ICMJE
 (submitted: April 23, 2019)
  • 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.
  • 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 23, 2019)
  • 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
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Fibroblast Specific Inhibition of LOXL2 and TGFbeta1 Signaling in Patients With Pulmonary Fibrosis.
Official Title  ICMJE Fibroblast Specific Inhibition of LOXL2 and TGFbeta1 Signaling in Patients With Pulmonary Fibrosis.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description:
Open Label
Primary Purpose: Other
Condition  ICMJE Idiopathic Pulmonary Fibrosis
Intervention  ICMJE Drug: Epigallocatechin-3-gallate (EGCG)
Epigallocatechin-3-gallate (EGCG) capsules
Other Name: Teavigo
Study Arms  ICMJE 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

Intervention: Drug: Epigallocatechin-3-gallate (EGCG)
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 TGFβ1-Driven Profibrotic State in Patients with Pulmonary Fibrosis. N Engl J Med. 2020 Mar 12;382(11):1068-1070. doi: 10.1056/NEJMc1915189.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 23, 2019)
35
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Hal A Chapman, MD 415-514-1210 Hal.Chapman@ucsf.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03928847
Other Study ID Numbers  ICMJE 17-23008
R01HL142265 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of California, San Francisco
Study Sponsor  ICMJE University of California, San Francisco
Collaborators  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: Hal A Chapman, MD UC San Francisco
PRS Account University of California, San Francisco
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP