Idiopathic Pulmonary Fibrosis
Conditions
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.
Interventions
Epigallocatechin-3-gallate (EGCG) capsules
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Hal Chapman
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Masking description
Open Label
Eligibility
Sex/Gender
ALL
Age
40 Years to 70 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference of Biomarker Snail1 Between EGCG-treated and Non-treated Patient Groups | 14 days | 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. |
| EGCG PK Level in Healthy Volunteers | 0, 0.5, 2, 4 hours after EGCG | 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). |
| Change of Serum Biomarker COMP Before and After EGCG Treatment in ILD Patients | Day 1 to day 14 | Change from baseline to day 14 in serum biomarkers associated with IPF, Cartilage Oligomeric Matrix Protein (COMP) measured by ELISA. |
| Change of Serum Biomarker Periostin Before and After EGCG Treatment in ILD Patients | Day 1 to day 14 | Change from baseline to day 14 in serum biomarkers associated with IPF, Periostin measured by ELISA. |
| Difference of Biomarker Collagen I Between EGCG-treated and Non-treated Patient Groups | 14 days | 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. |
| Difference of Biomarker p-Smad3 Between EGCG-treated and Non-treated Patient Groups | 14 days | 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. |
Countries
United States
Participant flow
Recruitment details
Healthy volunteer recruitment started in 12/1/2017 and ended in 3/30/2018. Subjects were recruited from UCSF community. Advertisements were posted around the campus. Patients recruitment started in 6/1/2018 and ended in 12/20/2018. Subjects were recruited from UCSF and UC Davis ILD clinics.
Participants by arm
| Arm | Count |
|---|---|
| EGCG PK in Healthy Volunteers 450 mg Healthy volunteers: 450 mg Epigallocatechin-3-gallate (EGCG) capsules administered once daily by mouth
Epigallocatechin-3-gallate (EGCG): 3 EGCG capsules | 5 |
| EGCG PK in Healthy Volunteers 600 mg Healthy volunteers: 600 mg Epigallocatechin-3-gallate (EGCG) capsules administered once daily by mouth
Epigallocatechin-3-gallate (EGCG): 4 EGCG capsules | 5 |
| EGCG PK in Healthy Volunteers 750 mg Healthy volunteers: 750 mg Epigallocatechin-3-gallate (EGCG) capsules administered once daily by mouth
Epigallocatechin-3-gallate (EGCG): 5 EGCG capsules | 5 |
| No Treatment Control in ILD Patients ILD patients that were not treated with EGCG are used as controls. | 10 |
| EGCG Treatment in ILD Patients Patients: 600 mg EGCG capsules once daily by mouth for two weeks
Epigallocatechin-3-gallate (EGCG): 4 EGCG capsules | 10 |
| Total | 35 |
Baseline characteristics
| Characteristic | EGCG PK in Healthy Volunteers 450 mg | Total | EGCG Treatment in ILD Patients | No Treatment Control in ILD Patients | EGCG PK in Healthy Volunteers 750 mg | EGCG PK in Healthy Volunteers 600 mg |
|---|---|---|---|---|---|---|
| Age, Customized | 64 years | 64 years | 65 years | 64 years | 68 years | 62 years |
| High-resolution computed tomography (HRCT) imaging indicative of lung fibrosis | 0 Participants | 20 Participants | 10 Participants | 10 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 12 Participants | 1 Participants | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 23 Participants | 9 Participants | 6 Participants | 3 Participants | 3 Participants |
| Region of Enrollment South Korea | 0 participants | 4 participants | 0 participants | 4 participants | 0 participants | 0 participants |
| Region of Enrollment United States | 5 participants | 31 participants | 10 participants | 6 participants | 5 participants | 5 participants |
| Sex: Female, Male Female | 3 Participants | 20 Participants | 6 Participants | 5 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 15 Participants | 4 Participants | 5 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 10 | 0 / 10 |
Outcome results
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.
Time frame: Day 1 to day 14
Population: Serum biomarker COMP was measured by ELISA and compared before and after EGCG treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EGCG PK in Healthy Volunteers 450 mg | Change of Serum Biomarker COMP Before and After EGCG Treatment in ILD Patients | Before EGCG treatment | 137.2 ng/ml | Standard Deviation 53.8 |
| EGCG PK in Healthy Volunteers 450 mg | Change of Serum Biomarker COMP Before and After EGCG Treatment in ILD Patients | After EGCG treatment | 97.9 ng/ml | Standard Deviation 26.9 |
p-value: <0.01Wilcoxon (Mann-Whitney)
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.
Time frame: Day 1 to day 14
Population: Serum biomarker Periostin was measured by ELISA and compared before and after EGCG treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EGCG PK in Healthy Volunteers 450 mg | Change of Serum Biomarker Periostin Before and After EGCG Treatment in ILD Patients | Before EGCG treatment | 41.9 ng/ml | Standard Deviation 15.9 |
| EGCG PK in Healthy Volunteers 450 mg | Change of Serum Biomarker Periostin Before and After EGCG Treatment in ILD Patients | After EGCG treatment | 35.2 ng/ml | Standard Deviation 11.7 |
p-value: <0.01Wilcoxon (Mann-Whitney)
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.
Time frame: 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EGCG PK in Healthy Volunteers 450 mg | Difference of Biomarker Collagen I Between EGCG-treated and Non-treated Patient Groups | 0.894 percentage of reference sample | Standard Deviation 0.375 |
| ECGC PK in Healthy Volunteers 600 mg | Difference of Biomarker Collagen I Between EGCG-treated and Non-treated Patient Groups | 0.136 percentage of reference sample | Standard Deviation 0.058 |
p-value: <0.01Kruskal-Wallis
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.
Time frame: 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EGCG PK in Healthy Volunteers 450 mg | Difference of Biomarker p-Smad3 Between EGCG-treated and Non-treated Patient Groups | 0.913 percentage of reference sample | Standard Deviation 0.201 |
| ECGC PK in Healthy Volunteers 600 mg | Difference of Biomarker p-Smad3 Between EGCG-treated and Non-treated Patient Groups | 0.284 percentage of reference sample | Standard Deviation 0.126 |
p-value: <0.01Kruskal-Wallis
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.
Time frame: 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EGCG PK in Healthy Volunteers 450 mg | Difference of Biomarker Snail1 Between EGCG-treated and Non-treated Patient Groups | 0.825 percentage of reference sample | Standard Deviation 0.332 |
| ECGC PK in Healthy Volunteers 600 mg | Difference of Biomarker Snail1 Between EGCG-treated and Non-treated Patient Groups | 0.132 percentage of reference sample | Standard Deviation 0.098 |
p-value: <0.01Kruskal-Wallis
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).
Time frame: 0, 0.5, 2, 4 hours after EGCG
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EGCG PK in Healthy Volunteers 450 mg | EGCG PK Level in Healthy Volunteers | 0 hour after EGCG | NA nM | — |
| EGCG PK in Healthy Volunteers 450 mg | EGCG PK Level in Healthy Volunteers | 0.5 hour after EGCG | 861 nM | Standard Deviation 761 |
| EGCG PK in Healthy Volunteers 450 mg | EGCG PK Level in Healthy Volunteers | 2 hours after EGCG | 1136 nM | Standard Deviation 666 |
| EGCG PK in Healthy Volunteers 450 mg | EGCG PK Level in Healthy Volunteers | 4 hours after EGCG | 659 nM | Standard Deviation 640 |
| ECGC PK in Healthy Volunteers 600 mg | EGCG PK Level in Healthy Volunteers | 4 hours after EGCG | 741 nM | Standard Deviation 226 |
| ECGC PK in Healthy Volunteers 600 mg | EGCG PK Level in Healthy Volunteers | 0 hour after EGCG | NA nM | — |
| ECGC PK in Healthy Volunteers 600 mg | EGCG PK Level in Healthy Volunteers | 2 hours after EGCG | 2266 nM | Standard Deviation 2174 |
| ECGC PK in Healthy Volunteers 600 mg | EGCG PK Level in Healthy Volunteers | 0.5 hour after EGCG | 612 nM | Standard Deviation 531 |
| EGCG PK in Healthy Volunteers 750 mg | EGCG PK Level in Healthy Volunteers | 4 hours after EGCG | 702 nM | Standard Deviation 293 |
| EGCG PK in Healthy Volunteers 750 mg | EGCG PK Level in Healthy Volunteers | 0.5 hour after EGCG | 3126 nM | Standard Deviation 4159 |
| EGCG PK in Healthy Volunteers 750 mg | EGCG PK Level in Healthy Volunteers | 2 hours after EGCG | 1582 nM | Standard Deviation 536 |
| EGCG PK in Healthy Volunteers 750 mg | EGCG PK Level in Healthy Volunteers | 0 hour after EGCG | NA nM | — |