Dose Ranging Study of Oral Epigallocatechin-3-gallate (EGCG) Given Daily for 12 Weeks to Patients With Idiopathic Pulmonary Fibrosis (IPF) Evaluating Safety, PK Interactions With Standard of Care Drugs, and Biomarkers of Drug Effect
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 50
- 试验地点
- 7
- 主要终点
- Participants with treatment-emergent adverse event (TEAE)
研究概览
简要总结
The primary purpose of this multi-center, double-blind, placebo-controlled, dose-ranging Phase I study is to assess the safety of a purified from green tea, EGCG, in patients with idiopathic pulmonary fibrosis (IPF) as a potential novel treatment for pulmonary fibrosis.
详细描述
This is a multi-center, double-blind, placebo-controlled, dose-ranging Phase I study of once daily EGCG administered for 12 weeks. The study will assess safety, pharmacokinetics, and biomarker measurements of drug effect in IPF patients already receiving background therapy for IPF with either nintedanib or pirfenidone. Two different doses of EGCG will be studied.
The rationale for this study is 1) extensive pre-clinical data in mice that EGCG is efficacious in attenuating pulmonary fibrosis by blocking collagen cross-linking and the pro-fibrotic pathway mediated by TGFβ1 signaling and 2) 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
All participants will be on one of the standard of care drugs (nintedanib or pirfenidone) and blindly given EGCG or placebo.
入排标准
- 年龄范围
- 40 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provision of signed and dated informed consent form.
- •Stated willingness to comply with all study procedures and availability for the duration of the study.
- •Male or female, aged 40-85 years old.
- •Participant has IPF satisfying the 2022 ATS diagnostic criteria, confirmed by enrolling investigator at Visit
- •Participant must have been on a stable dose of nintedanib twice daily or pirfenidone three times daily dose for at least 12 weeks prior to baseline (Visit 2).
- •Participant has a FVC ≥ 50% predicted using the global lung function initiative (GLI).
- •Participant has a DLCO corrected for hemoglobin ≥ 35% predicted using the GLI.
- •Women of child bearing potential (WCBP), defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 24 consecutive months if < 55 years or 12 months if > 55 years, must have a negative serum pregnancy test within 1 week prior to the first dose of study drug and must agree to use adequate methods of birth control throughout the study. Adequate methods of contraception include use of oral contraceptives or Depo-Provera, with an additional barrier method (diaphragm with spermicidal gel or condoms with spermicide), double-barrier methods (diaphragm with spermicidal gel and condoms with spermicide), partner vasectomy, and total abstinence.
- •Participant has a life expectancy of at least 9 months at Visit
- •Ability to take oral medication and be willing to adhere to EGCG regimen.
- •Agreement to refrain from drinking green tea in excess of a cup a day or eating green tea extract for 4 weeks before baseline and during the trial.
排除标准
- •AST, ALT, or direct bilirubin above upper limit normal from any cause at the Screening Visit.
- •Any history of HCV or HBV infection, NASH/NAFLD, or cirrhosis.
- •Alcohol consumption greater than 7 drinks per week.
- •Participant has emphysema ≥ 50% or the extent of emphysema is greater than the extent of fibrosis as per interpretation of Site Investigator or radiologist.
- •Participant has received investigational therapy for IPF within 4 weeks before baseline (Visit 2).
- •Participant is receiving systemic corticosteroids equivalent to prednisone > 10 mg/day or equivalent within 2 weeks of baseline visit (Visit 2).
- •Participant has any concurrent condition other than IPF that, in the Investigator's opinion, is unstable and/or would impact the likelihood of survival for the study duration or the participant's ability to complete the study as designed, or may influence any of the safety or efficacy assessments included in the study.
- •Participant has baseline resting oxygen saturation of < 89% on room air or need for continuous oxygen use at baseline visit (Visit 2).
- •Consumption of GTE products in excess of a cup of green tea a day within one month of the baseline visit (Visit 2).
- •Participant is receiving digoxin at the time of screening (Visit 1) and for the duration of the study.
- •Active respiratory infection requiring treatment with antibiotics within 4 weeks of the baseline visit (Visit 2).
- •Likely to be listed for transplant during trial participation.
研究组 & 干预措施
Placebo for EGCG 300 mg
Patients enrolled in this group will be given oral capsule Placebo daily for 12 weeks with doctor provided Nintedanib or Pirfenidone. The number of placebo capsules will be equal to that of 300 mg EGCG.
干预措施: Placebo 2 capsules + Nintedanib or Pirfenidone (Combination Product)
EGCG 600 mg with Nintedanib
Patients enrolled in this group will be given oral capsule EGCG 600 mg daily with doctor provided Nintedanib for 12 weeks.
干预措施: EGCG 600 mg + Nintedanib (Combination Product)
EGCG 600 mg with Pirfenidone
Patients enrolled in this group will be given oral capsule EGCG 300 mg daily with doctor provided Pirfenidone for 12 weeks.
干预措施: EGCG 600 mg + Pirfenidone (Combination Product)
EGCG 300 mg with Nintedanib
Patients enrolled in this group will be given oral capsule EGCG 300 mg daily with doctor provided Nintedanib for 12 weeks.
干预措施: EGCG 300 mg + Nintedanib (Combination Product)
EGCG 300 mg with Pirfenidone
Patients enrolled in this group will be given oral capsule EGCG 300 mg daily with doctor provided Pirfenidone for 12 weeks.
干预措施: EGCG 300 mg + Pirfenidone (Combination Product)
Placebo for EGCG 600 mg
Patients enrolled in this group will be given oral capsule Placebo daily for 12 weeks with doctor provided Nintedanib or Pirfenidone. The number of placebo capsules will be equal to that of 600 mg EGCG.
干预措施: Placebo 4 capsules + Nintedanib or Pirfenidone (Combination Product)
结局指标
主要结局
Participants with treatment-emergent adverse event (TEAE)
时间窗: Up to 12 weeks
The number of participants with at least 1 treatment-emergent adverse event
The number of grade 3 or 4 treatment-emergent adverse events (TEAE)
时间窗: Up to 12 weeks
The number of grade 3 or 4 treatment-emergent adverse events
Participants with serious adverse event (SAE)
时间窗: Up to 12 weeks
The number of participants with at least 1 serious adverse event
Participants died due to adverse events (AE) within 4 weeks of discontinuation
时间窗: Up to 12 weeks
The number of participants who died due to adverse events within 4 weeks of discontinuation from study treatment
Adverse events (AE) by causality
时间窗: Up to 12 weeks
The number of adverse events by causality (reasonable possibility/no reasonable possibility)
Change in total score for the King's Brief Interstitial Lung Disease (K-BILD) Questionnaire
时间窗: Up to 12 weeks
Absolute change in total score for the King's Brief Interstitial Lung Disease (K-BILD) Questionnaire from baseline at day 84
Participants with an absolute change in K-BILD of 5 points or more in either direction
时间窗: Up to 12 weeks
The number of participants with an absolute change in K-BILD from baseline to day 84 of 5 points or more in either direction
Participants with grade 3 or 4 treatment-emergent adverse events (TEAE)
时间窗: Up to 12 weeks
The number of participants with at least 1 grade 3 or 4 treatment-emergent adverse events
Participants with discontinued study treatment due to serious adverse events (SAE)
时间窗: Up to 12 weeks
The number of participants who discontinued study treatment due to serious adverse events
Participants died due to adverse events (AE) on study treatment
时间窗: Up to 12 weeks
The number of participants who died due to adverse events on study treatment
Change in forced vital capacity (FVC)
时间窗: Up to 12 weeks
Absolute and relative change in forced vital capacity from baseline at day 84
Participants with a peak level change for nintedanib or pirfenidone over 50% from screening to baseline (day 1)
时间窗: Day 1
The number of participants with a change from screening to baseline (day 1) in peak levels for nintedanib or pirfenidone of 50% or more in either direction
Participants with a trough level change for nintedanib or pirfenidone over 50% from baseline to day 14
时间窗: Day 14
The number of participants with a change from baseline to day 14 in trough levels for nintedanib or pirfenidone of 50% or more in either direction
Participants with an absolute change of at least 1.5 points for the LCQ
时间窗: Up to 12 weeks
The number of participants with an absolute change from baseline to day 84 of 1.5 points or more in either direction for the LCQ
The number of treatment-emergent adverse events (TEAE)
时间窗: Up to 12 weeks
The number of treatment-emergent adverse events
The number of serious adverse event (SAE)
时间窗: Up to 12 weeks
The number of serious adverse events
Participants with discontinued study treatment due to adverse events (AE)
时间窗: Up to 12 weeks
The number of participants who discontinued study treatment due to adverse events
Participants with adverse event (AE) by causality
时间窗: Up to 12 weeks
The number of participants with at least 1 adverse event by causality (reasonable possibility/no reasonable possibility)
Change in forced vital capacity (FVC) % predicted
时间窗: Up to 12 weeks
Absolute and relative change in forced vital capacity % predicted from baseline at day 84
Change in diffusing capacity for carbon monoxide (DLCO)
时间窗: Up to 12 weeks
Absolute and relative change in diffusing capacity for carbon monoxide uncorrected for hemoglobin from baseline at day 84
Change in total score for the Leicester Cough Questionnaire (LCQ)
时间窗: Up to 12 weeks
Absolute change in total score for the Leicester Cough Questionnaire (LCQ) from baseline at day 84
Participants with peak (cmax) levels for EGCG < 250 nM at day 14
时间窗: Day 14
The number of participants with peak (cmax) levels for EGCG \< 250 nM at day 14
Change in individual laboratory parameters
时间窗: Up to 12 weeks
Absolute and relative change in individual laboratory parameters from baseline at day 84
Participants with a peak level change for nintedanib or pirfenidone over 50% from baseline to day 14
时间窗: Day 14
The number of participants with a change from baseline to day 14 in peak levels for nintedanib or pirfenidone of 50% or more in either direction
次要结局
- Change of serum biomarker COMP at day 14(Day 14)
- Change of serum biomarker pro-MMP1 at day 84(Day 84)
- Change of serum biomarker COMP at day 84(Day 84)
- Change of serum biomarker Periostin at day 14(Day 14)
- Change of serum biomarker pro-MMP1 at day 14(Day 14)
- Change of serum biomarker Periostin at day 84(Day 84)
研究者
Hal Chapman
Professor
University of California, San Francisco