EGCG for Pulmonary Fibrosis
Recruiting in Palo Alto (17 mi)
+2 other locations
Overseen byFernando Martinez, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Hal Chapman
Disqualifiers: Pregnancy, Radiation exposure, Implants, others
Trial Summary
What is the purpose of this trial?The primary purpose of this substudy is to determine if collagen-targeted PET using the type 1 collagen-targeted PET probe, Gallium-68 (68Ga)-labeled collagen binding probe 8 (CBP8) can inform as to drug effect of EGCG and assist in dose selection.
Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, it does mention evaluating interactions with standard care drugs, so it's best to discuss your current medications with the trial team.
What data supports the effectiveness of the treatment 68Ga-CBP8 for pulmonary fibrosis?
Research shows that 68Ga-CBP8, a probe that targets collagen, is effective in detecting and monitoring pulmonary fibrosis in animal models. It has shown high specificity for lung scarring and correlates well with the amount of lung collagen, making it a promising tool for noninvasive imaging of pulmonary fibrosis in humans.
12345Is 68Ga-CBP8 safe for use in humans?
In a study with nine healthy volunteers, 68Ga-CBP8 was found to be safe with no adverse effects reported. It showed rapid clearance from the body, mainly through the kidneys, and had a safety profile similar to other gallium-based probes.
12345How does the drug EGCG differ from other treatments for pulmonary fibrosis?
EGCG, a component of green tea, is unique because it binds to specific proteins involved in cell adhesion, potentially reducing fibrosis by preventing cells from sticking to fibronectin, a protein that contributes to tissue scarring. This mechanism is different from other treatments that may not target cell adhesion directly.
12567Eligibility Criteria
This trial is for individuals with Pulmonary Fibrosis or Idiopathic Pulmonary Fibrosis. Specific eligibility criteria are not provided, but typically participants would need to meet certain health standards and may be required to have a confirmed diagnosis of the conditions mentioned.Inclusion Criteria
Enrolled in and eligible for the main EGCG Phase 1 study
Signed informed consent
Exclusion Criteria
My kidney function test shows an eGFR below 30.
Pregnant or breastfeeding (a negative quantitative serum human chorionic gonadotropin (hCG) pregnancy test is required for females having child-bearing potential before participation)
Research-related radiation exposure exceeds 50 millisievert (mSv) in the prior 12 months
+6 more
Participant Groups
The study is testing the effects of EGCG at two different doses (300 mg and 600 mg) compared to placebos. It uses a PET imaging probe called Gallium-68 (68Ga)-CBP8 to see if it can show how well EGCG works in treating fibrosis and help choose the right dose.
4Treatment groups
Active Control
Placebo Group
Group I: EGCG 300 mgActive Control2 Interventions
Patients enrolled in this group will be given oral capsule EGCG 300 mg daily with doctor provided anti-fibrotic for 12 weeks.
Group II: EGCG 600 mgActive Control2 Interventions
Patients enrolled in this group will be given oral capsule EGCG 600 mg daily with doctor provided anti-fibrotic for 12 weeks.
Group III: Placebo for EGCG 300 mgPlacebo Group2 Interventions
Patients enrolled in this group will be given oral capsule Placebo daily for 12 weeks with doctor provided anti-fibrotic. The number of placebo capsules will be equal to that of 300 mg EGCG.
Group IV: Placebo for EGCG 600 mgPlacebo Group2 Interventions
Patients enrolled in this group will be given oral capsule Placebo daily for 12 weeks with doctor provided anti-fibrotic. The number of placebo capsules will be equal to that of 600 mg EGCG.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of MichiganAnn Arbor, MI
University of VirginiaCharlottesville, VA
Massachusetts General HospitalBoston, MA
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Who Is Running the Clinical Trial?
Hal ChapmanLead Sponsor
Cornell UniversityCollaborator
National Heart, Lung, and Blood Institute (NHLBI)Collaborator
Massachusetts General HospitalCollaborator
University of MichiganCollaborator
References
Type I collagen-targeted PET probe for pulmonary fibrosis detection and staging in preclinical models. [2018]Pulmonary fibrosis is scarring of the lungs that can arise from radiation injury, drug toxicity, environmental or genetic causes, and for unknown reasons [idiopathic pulmonary fibrosis (IPF)]. Overexpression of collagen is a hallmark of organ fibrosis. We describe a peptide-based positron emission tomography (PET) probe (68Ga-CBP8) that targets collagen type I. We evaluated 68Ga-CBP8 in vivo in the bleomycin-induced mouse model of pulmonary fibrosis. 68Ga-CBP8 showed high specificity for pulmonary fibrosis and high target/background ratios in diseased animals. The lung PET signal and lung 68Ga-CBP8 uptake (quantified ex vivo) correlated linearly (r2 = 0.80) with the amount of lung collagen in mice with fibrosis. We further demonstrated that the 68Ga-CBP8 probe could be used to monitor response to treatment in a second mouse model of pulmonary fibrosis associated with vascular leak. Ex vivo analysis of lung tissue from patients with IPF supported the animal findings. These studies indicate that 68Ga-CBP8 is a promising candidate for noninvasive imaging of human pulmonary fibrosis.
Biodistribution, Dosimetry, and Pharmacokinetics of 68Ga-CBP8: A Type I Collagen-Targeted PET Probe. [2023]The 68Ga-Collagen Binding Probe #8, 68Ga-CBP8, is a peptide-based, type I collagen-targeted probe developed for imaging of tissue fibrosis. The aim of this study was to determine the biodistribution, dosimetry, and pharmacokinetics of 68Ga-CBP8 in healthy human subjects. Methods: Nine healthy volunteers (5 male and 4 female) underwent whole-body 68Ga-CBP8 PET/MRI using a Biograph mMR scanner. The subjects were imaged continuously for up to 2 h after injection of 68Ga-CBP8. A subset of subjects underwent an additional imaging session 2-3 h after probe injection. OLINDA/EXM software was used to calculate absorbed organ and effective dose estimates based on up to 17 regions of interest (16 for men) defined on T2-weighted MR images and copied to the PET images, assuming a uniform distribution of probe concentration in each region. Serial blood sampling up to 90 min after probe injection was performed to assess blood clearance and metabolic stability. Results: The mean injected activity (±SD) of 68Ga-CBP8 was 220 ± 100 MBq (range, 113-434 MBq). No adverse effects related to probe administration were detected. 68Ga-CBP8 demonstrated an extracellular distribution with predominantly rapid renal clearance. Doses on the urinary bladder were 0.15 versus 0.19 mGy/MBq for men versus women. The highest absorbed doses for the rest of the organs were measured in the kidneys (0.078 vs. 0.088 mGy/MBq) and the liver (0.032 vs. 0.041 mGy/MBq). The mean effective dose was 0.018 ± 0.0026 mSv/MBq using a 1-h voiding model. The 68Ga-CBP8 signal in the blood demonstrated biexponential pharmacokinetics with an initial distribution half-life of 4.9 min (95% CI, 2.4-9.4 min) and a 72-min elimination half-life (95% CI, 47-130 min). The only metabolite observed had a long blood plasma half-life, suggesting protein-bound 68Ga. Conclusion: 68Ga-CBP8 displays favorable in-human characteristics and dosimetry similar to that of other gallium-based probes. 68Ga-CBP8 could therefore be used for noninvasive collagen imaging across a range of human fibrotic diseases.
Molecular imaging of fibrosis using a novel collagen-binding peptide labelled with 99mTc on SPECT/CT. [2018]Fibrosis, closely related to chronic various diseases, is a pathological process characterised by the accumulation of collagen (largely collagen type I). Non-invasive methods are necessary for the diagnosis and follow-up of fibrosis. This study aimed to develop a collagen-targeted probe for the molecular imaging of fibrosis. We identified CPKESCNLFVLKD (CBP1495) as an original collagen-binding peptide using isothermal titration calorimetry and enzyme-linked immunosorbent assay. CBP1495 effectively bound to collagen type I (K d = 861 nM) and (GPO)9 (K d = 633 nM), a collagen mimetic peptide. Western blot and histochemistry validated CBP1495 targeting collagen in vitro and ex vivo. (Gly-(D)-Ala-Gly-Gly) was introduced to CBP1495 for coupling 99mTc. Labelling efficiency of 99mTc-CBP1495 was 95.06 ± 1.08 %. The physico-chemical properties, tracer kinetics and biodistribution of 99mTc-CBP1495 were carried out, and showed that the peptide stably chelated 99mTc in vitro and in vivo. SPECT/CT imaging with 99mTc-CBP1495 was performed in rat fibrosis models, and revealed that 99mTc-CBP1495 significantly accumulated in fibrotic lungs or livers of rats. Finally, 99mTc-CBP1495 uptake and hydroxyproline (Hyp), a specific amino acid of collagen, were quantitatively analysed. The results demonstrated that 99mTc-CBP1495 uptake was positvely correlated with Hyp content in lungs (P < 0.0001, r 2 = 0.8266) or livers (P < 0.0001, r 2 = 0.7581). Therefore, CBP1495 is a novel collagen-binding peptide, and 99mTc-labelled CBP1495 may be a promising radiotracer for the molecular imaging of fibrosis.
Improved Radiolytic Stability of a 68Ga-labelled Collagelin Analogue for the Imaging of Fibrosis. [2021]There is an unmet medical need for non-invasive, sensitive, and quantitative methods for the assessment of fibrosis. Herein, an improved collagelin analogue labelled with gallium-68 for use with positron emission tomography (PET) is presented. A cyclic peptide, c[CPGRVNleHGLHLGDDEGPC], was synthesized by solid-phase peptide synthesis, conjugated to 2-(4,7-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7-triazonan-1-yl)acetic acid, and labelled with gallium-68. High performance liquid chromatography (HPLC) was used for the quality and stability assessment of the collagelin analogue. Non-specific organ distribution, blood clearance, and excretion rates were investigated in healthy mice and rats using ex vivo organ distribution analysis and dynamic in vivo PET/CT. Mice with carbon tetrachloride (CCl4) induced liver fibrosis were used for the investigation of specific binding via in vitro frozen section autoradiography, ex vivo organ distribution, and in vivo PET/CT. A non-decay corrected radiochemical yield (48 ± 6%) of [68Ga]Ga-NOTA-PEG2-c[CPGRVNleHGLHLGDDEGPC] ([68Ga]Ga-NO2A-[Nle13]-Col) with a radiochemical purity of 98 ± 2% was achieved without radical scavengers. The 68Ga-labelling was regioselective and stable at ambient temperature for at least 3 h. The autoradiography of the cryosections of fibrotic mouse liver tissue demonstrated a distinct heterogeneous radioactivity uptake that correlated with the fibrosis scores estimated after Sirius Red staining. The blood clearance and tissue washout from the [68Ga]Ga-NO2A-[Nle13]-Col was fast in both normal and diseased mice. Dosimetry investigation in rats indicated the possibility for 4-5 PET/CT examinations per year. Radiolytic stability of the collagelin analogue was achieved by the substitution of methionine with norleucine amino acid residue without a deterioration of its binding capability. [68Ga]Ga-NO2A-[Nle13]-Col demonstrated a safe dosimetry profile suitable for repeated scanning.
Optimization of a Collagen-Targeted PET Probe for Molecular Imaging of Pulmonary Fibrosis. [2020]There is a large unmet need for a simple, accurate, noninvasive, quantitative, and high-resolution imaging modality to detect lung fibrosis at early stage and to monitor disease progression. Overexpression of collagen is a hallmark of organ fibrosis. Here, we describe the optimization of a collagen-targeted PET probe for staging pulmonary fibrosis. Methods: Six peptides were synthesized, conjugated to a copper chelator, and radiolabeled with 64Cu. The collagen affinity of each probe was measured in a plate-based assay. The pharmacokinetics and metabolic stability of the probes were studied in healthy rats. The capacity of these probes to detect and stage pulmonary fibrosis in vivo was assessed in a mouse model of bleomycin-induced fibrosis using PET imaging. Results: All probes exhibited affinities in the low micromolar range (1.6 μM < Kd < 14.6 μM) and had rapid blood clearance. The probes showed 2- to 8-fold-greater uptake in the lungs of bleomycin-treated mice than sham-treated mice, whereas the distribution in other organs was similar between bleomycin-treated and sham mice. The probe 64Cu-CBP7 showed the highest uptake in fibrotic lungs and the highest target-to-background ratios. The superiority of 64Cu-CBP7 was traced to a much higher metabolic stability compared with the other probes. The specificity of 64Cu-CBP7 for collagen was confirmed by comparison with a nonbinding isomer. Conclusion:64Cu-CBP7 is a promising candidate for in vivo imaging of pulmonary fibrosis.
A gold-complex initiated functionalization of biologically active polyphenols applied to a 18F-labeled chemical probe. [2023](-)-Epigallocatechin gallate (EGCG), a key component of green tea, exerts therapeutic anticancer and antiallergic properties through its binding to the 67 kDa laminin receptor. The functionalization of EGCG is a promising strategy for creating new drug candidates and chemical probes. In our study, we developed a method for effectively modifying the A ring of EGCG through an electrophilic aromatic substitution with amidomethyl 2-alkynylbenzoates initiated with a gold complex. The 2-alkynylbenzoates treated with (Ph3P)AuOTf under neutral conditions yielded N-acylimines. A further electrophilic aromatic substitution resulted in a mixture of EGCG substituted with acylaminomethyl groups at the 6 and 8 positions with a significant amount noted at the 6 position. We then explored the synthesis of 18F-labeled EGCG with a neopentyl labeling group, an effective labeling group for radiohalogens of not only fluorine-18 but also of astatine-211. To achieve this, we prepared precursors that possessed acid-sensitive protecting groups and base-unstable leaving groups using our established method. Substitution of EGCG with a neopentyl labeling group at either the C6 or C8 position did not affect its anticancer efficacy in U266 cells. Finally, we investigated the preparation of 18F-labeled EGCG. The 18F-fluorination of a mixture of 6- and 8-substituted precursors yielded the corresponding 18F-labeled compounds in 4.5% and 3.0% radiochemical yields (RCYs), respectively. Under acidic conditions, the 18F-labeled 8-substituted compound produced 18F-labeled EGCG in 37% RCY, which heralds the potential of our functionalization approach.
Interaction between the carboxyl-terminal heparin-binding domain of fibronectin and (-)-epigallocatechin gallate. [2013]We have previously reported that (-)-epigallocatechin gallate (EGCg) inhibited lung carcinoma cell adhesion to fibronectin (FN) and demonstrated its interaction with FN. In the present work, we studied the interaction between thermolysin fragments of FN and EGCg. An amino acid sequence analysis of the fragment bound by EGCg-agarose provided its identification as a carboxyl-terminal heparin-binding domain. Thus, the inhibition of cancer cell adhesion to FN by EGCg is not caused by its direct binding to the cell-binding domain containing an Arg-Gly-Asp-sequence.