Study of Oral Epigallocatechin-3-gallate (EGCG) in IPF Patients

This interventional study will test whether a low cost and largely non-toxic small molecule, purified from green tea, EGCG, is safe when given to IPF patients with mild-moderate disease and without significant interactions with standard of care drugs. The rationale for the study is, first, the extensive prior pre-clinical data in mice that the trihydroxyphenolic EGCG is efficacious in attenuating pulmonary fibrosis by blocking collagen cross-linking and the pro-fibrotic pathway mediated by TGFβ1 signaling. More compelling are recently published data demonstrating that in humans EGCG is safe and capable of blocking lung tissue pro-fibrotic signaling when given two weeks prior to diagnostic surgical biopsy of pulmonary fibrosis patients, many of whom were subsequently diagnosed with IPF. Changes in three blood markers reflecting TGFβ signaling were also consistent with attenuation of signaling by EGCG in vivo in these patients. However, EGCG has never been given for longer than two weeks to IPF patients. The study aims to assess the safety in patients given daily oral EGCG over 12 weeks with the IPF drugs, pirfenidone and nintedanib. Eligible patients will be enrolled in one of four groups: EGCG 400 mg with pirfenidone (n= 10 per group), EGCG 400 mg with nintedanib (n= 10 per group), placebo with Nintedanib (n= 5 per group), placebo with Pirfenidone (n= 5 per group). If no safety concerns, in terms of adverse events or significant drug-drug interactions, are raised after all subjects in a group have completed 12 weeks of treatment and 4 weeks of follow-up, enrollment will begin into the higher dose group. 2 additional groups will be enrolled: EGCG 600 mg with pirfenidone (n= 10 per group), EGCG 600 mg with nintedanib (n= 10 per group). The total duration of trial for each group will be 12 weeks of treatment and 4 weeks of follow-up assuming no study-limiting adverse events or significant drug-drug interactions. Study participants will be followed closely for the development of treatment-related adverse events, especially hepatotoxicity. Participants will also be tested for the impact of EGCG on the expected (peak and trough) blood levels of nintedanib or pirfenidone and vice versa. Each group will have blood drawn on days 1, 14, and 84 to compare pre-determined biomarker changes as a possible determinant of dosing in a future phase II trial.

Study Design: This is a multi-center, randomized-controlled, dose-ranging Phase I study for EGCG safety, PK, and biomarker measurements in IPF patients. The trial includes a one-week screening period, 12-week treatment period, and a 4-week safety follow-up period. Fifty patients ages 40-85 years old with a diagnosis of IPF on stable dose pirfenidone or nintedanib will be consented. Consented patients will be assigned to 1 of 5 groups (EGCG 400 mg plus nintedanib, EGCG 400 mg plus pirfenidone, EGCG 600 mg plus nintedanib, EGCG 600 mg plus pirfenidone, or placebo plus nintedanib or pirfenidone) to receive once daily EGCG capsules or placebo orally with pirfenidone or nintedanib for 12 weeks. Study Design Rationale: Due to the excellent suggestions of the reviewers the investigators have modified our study design to a randomized controlled, double-blinded study design. Our selected design maximizes information about EGCG for safety assessments because all participants who receive EGCG treatment do so concurrent with standard of care therapy (nintedanib or pirfenidone). While a daily dose of 600 mg was utilized in our strong preliminary data demonstrating an effect of EGCG on pro-fibrotic signaling with two weeks of EGCG, these patients were not on treatment with either pirfenidone or nintedanib. Thus, the investigators propose starting with a lower dose of EGCG (400 mg) given that all patients will be concurrently on these agents and then increasing to 600 mg of EGCG in a different group of subjects only after a staged safety analysis. The duration of 12 weeks treatment with 4 weeks follow-up was chosen to increase the time for capturing potential hepatoxicity. Study Intervention: The investigators plan to purchase >94% EGCG from Teavigo as before but as raw powder prior to encapsulation by Teavigo. Three lots of EGCG each sufficient for one year storage and use will be purchased in years 1-3. EGCG will be encapsulated as 200 mg capsules in the investigational drug pharmacy at Temple University, along with matching placebo capsules. Representative EGCG 200 mg capsules will be analyzed by mass spectrometry by Covance (now Eurofins) to verify purity of EGCG and absence of contaminants such has caffeine prior to any distribution. Multiple lots of >94% EGCG previously obtained from Teavigo and analyzed by Covance have proven to be as advertised. Placebo capsules will be assayed for absence of EGCG. Centralized investigational drug management will also be coordinated by the investigational drug pharmacy at Temple University as part of the Data Coordinating Center. An accurate and current accounting of the dispensing and return of study drug for each subject will be maintained on an ongoing basis by a member of the study site staff. The number of study drug dispensed and returned by the subject will be recorded on the Investigational Drug Accountability Record. The clinical monitor will verify these documents throughout the course of the study. Study drug (EGCG or placebo) will only be dispensed to patients who meet the eligibility criteria and are assigned to a treatment group in the trial. The Investigator will maintain a patient Drug Dispensing Log detailing numbers and dates of study drug used for each patient during the course of the trial. The dispensing will be captured in the eCRF and will be verified. A site Drug Accountability Log will also be maintained by site personnel. The log will be signed off by the Investigator at the end of the trial. Participants will be asked to keep a patient diary noting the day and date they take their study drug and any adverse events. They will be asked to bring their patient diary to the last visit along with all used and unused study drug containers. Recruitment: Patients presenting to clinics at these sites with a final diagnosis of IPF, meeting above eligibility criteria, and interested in participating, will be consented. Potential patients are required to undergo a Screening Visit prior to allocation to a treatment group. Each participant will receive a unique subject ID which must be entered in a screening log. The subject IDs will be allocated sequentially and also entered in the electronic case record form, along with the reason for screening failure if the participant is not allocated to a treatment group. Participants screened in the trial will be permitted to be re-screened once in this trial, except those who need a run-in period to stabilize the dose of concomitant treatment per protocol. Study visits: Participants will be contacted eight times over the course of 16 weeks; five of these visits will be in person (Screening and Days 1, 14, 28 and 84) while three (Days 7 and 56, and Follow-up ) will be remote. Participants will receive EGCG once daily one hour before breakfast whereas nintedanib or pirfenidone will be taken as prescribed with morning breakfast. Participants will be asked to hold their morning dose of nintedanib or pirfenidone on day 1 and 14 for pharmacokinetic analyses. All participants will have blood drawn prior to first EGCG drug doses and sera stored at -80oC for future analyses. Additional sera collected at screening, days 7, 14, 28, 84 and follow-up will be tested for hematologic and/or chemistry panels including liver chemistries. Sera will also be collected on day 1 and 14 for pharmacokinetic analyses and on day 1, 14, and 84 for prespecified biomarker analyses. All safety-related lab tests will be completed either at the in-person visits or at local labs near the participants and results reported to the DCC. Serum aliquots for biomarker and drug level determinations will be frozen and shipped to UCSF. A subgroup of participants enrolled will undergo PET imaging with 68Ga-CBP8 prior to EGCG initiation and at completion of 12 weeks of EGCG therapy.