扶正化瘀美国二期临床

null扶正化瘀治疗丙肝肝纤维化 的随机、双盲、安慰剂对照的多中心二期临床实验扶正化瘀治疗丙肝肝纤维化 的随机、双盲、安慰剂对照的多中心二期临床实验 研究者发起的临床实验 主要研究者: 哈桑尼, MD, FACP, FACG, AGAF 加州大学圣地亚哥分校医学院 医学教授 南加州肝病中心主任，肝病临床试验中心主任原理原理HCV induce liver fibrosis Failure to eliminate the virus results in progressive fibrosis No approved anti-fibrotic agents Bench research is exploring the potential of many anti-fibrotic agents Fuzhenghuaya is an oral botanical formula with limited side effects and proven efficacy against hepatic fibrosis in animal models and in patients with chronic liver disease主要目的主要目的To establish the safety of FZHY (vitals, PE, adverse events, conco. meds, labs) To establish the efficacy of FZHY in improving the liver fibrosis stage and degree of inflammation (Ishack Score) in patients with HCV who have: Failed prior anti-HCV therapy or Cannot receive Interferon therapy or Refused Interferon based therapy次要目的次要目的To describe changes in immunohistochemical markers of fibrogenesis (markers of HSC activation) To describe changes in liver histology over 48 weeks of therapy with FZHY ( HAI, Steatosis) To explore the relationships between serum markers of hepatic fibrosis, changes in histology and treatment with FZHY To characterize the effect of FZHY on serum HCV RNA To characterize the effect of FZHY on liver injury tests (ALT, AST, AP, GGT, bilirubin, albumin) To characterize the effect of FZHY on blood picture (WBC, RBC, Hb, Hct, MCV, Plt) Effects of FZHY on QOL and cognitive measures研究设计研究设计Investigator Initiated study A Double blinded, Randomized, Placebo-controlled, Phase II Study Group A: FZHY (4.8 gms) Group B: Placebo Multi-Center (7-10) Screening Period: maximum of 60 days Baseline: Randomization and start of FZHY/Placebo Study drug phase: 48 weeks (1 year) Follow-up phase: 12 weeks (3 months)双盲双盲This is a double-blinded study; the study manager is the only person who will know which group of the study a patient is in. Only in the case of an emergency and if the knowledge of the investigational product is essential for the clinical management or welfare of the subject, the investigator may request unblinding of the subject’s treatment assignment. 随机随机Patients are randomized to: Group A and Group B in a 1:1 ratio. Randomization is centralized and is accessed via IVRS.研究人群研究人群A total of 100 subjects – 50 subjects in each group. Sample size determined to achieve a moderate effect size with 90% power and an alpha level of 0.05 Sample includes a 10% drop-out rate patient did not meet inclusion/exclusion criteria or did not complete treatment入选入选标准A subject will be eligible for inclusion in this study only if all of the following criteria apply: Age between 18 and 70 years, inclusive. Documented positive serology for HCV antibody Serum HCV RNA positive at or before the pre-screening visit A biopsy with a documented Ishak fibrosis score of 2, 3 or 4 as determined by the local or central pathologist (within 1 year)入选标准 入选标准 Failure to achieve sustained virologic response (SVR) with previous interferon (standard or pegylated) and ribavirin treatment or patients who could not tolerate interferons or refused Interferon-based therapy. Prior treatment with interferon/ribavirin must have been discontinued at least 6 months Negative urine pregnancy tests (for women of child bearing potential) Availability and willingness of subject to provide written informed consent排除标准排除标准A subject will not be eligible for inclusion in this study if any of the following criteria apply: History of hepatic decompensation Co-infection with HBV or HIV Liver histology consistent with any other co-existing cause of chronic liver disease (steatosis >33%) Documented evidence of a hepatic mass lesion suspicious for hepatocellular carcinoma Alpha-fetoprotein > 200ng/mL at pre-screening排除标准排除标准Inadequate hematologic function defined by any of the following: Hemoglobin<12 gm/dl Absolute Neutrophil Count (ANC) <1.0 x 103/L Platelet < 75,000/L. Serum creatinine >1.5mg/dL (≥130µmol/L), Calculated creatinine clearance <60mL/min (Cockcroft and Gault) Serum ALT level ≥5 x ULN Albumin <3.2g/dL Total bilirubin >1.2 x ULN Prothrombin time > 15 seconds or International normalized ratio (INR) > 1.3 Organ, stem cell, or bone marrow transplant排除标准排除标准Serious concurrent medical illness that in the investigator’s opinion might interfere with therapy other than liver disease such as uncontrolled DM Active systemic autoimmune disorder Other medical conditions that, in the investigator’s opinion, might interfere with compliance with therapy, participation in the study or interpretation of results Pregnancy (or lactation) or, in subjects capable of bearing children, inability/unwillingness to practice adequate contraception Therapy with systemic cytotoxic agents, immunomodulators, or immunosuppressive therapy requiring use of more than 5mg of prednisone (or its equivalent) per day排除标准排除标准Therapy with a systemic antiviral agent (with the exception of prophylaxis or treatment of influenza or chronic HSV) within the past 30 days Concurrent participation in another clinical trial in which the subject is or will be exposed to another investigational or a non-investigational drug or device within 30 days of the screening visit Known hypersensitivity to FZHY or to any component of the FZHY tablets Active alcohol abuse (>2 gm/day) within the past 1 year Patients, who in the opinion of the Investigator or Sponsor, are not suitable candidates for enrollment or who would not comply with the requirements of the study. 扶正化瘀组方扶正化瘀组方扶正化瘀剂量扶正化瘀剂量Daily Dose of Fuzhenghuayu: 24 g of crude drug per dose were made into 15 seed capsules It can be said that every seed is 1.6g of crude drug The formula includes 8g of Radix Salvia Miltiorrhizae, 4 g of fermentation Mycelium powder, 2g of Semen Persicae, 6g of Gynostemma Pentaphyllammak, 2g of Fructus Schisandrae Chinesnsis, 2g of Pollen Pini扶正化瘀片扶正化瘀片Daily Dose = 4.5 gm (6 tablets) Divided for three times a day Each dose is 2 tablets Each tablets is 750 mg 试验药物用法试验药物用法The following treatments will be provided in this study: Group A = FZHY 2 tablets 3x/day Group B = Placebo 2 tablets 3x/day All doses should be taken after a meal Stored in room temperature Bottles of 150 tablets (labeled)筛选期筛选期Will be within 60 days from starting study drug After signing consent the following procedures will be done: Demographic data collection Review of medical history Blood draw EKG Liver biopsy and histology reviewBaseline visit and study drug phaseBaseline visit and study drug phaseBaseline visit is defined as the day the subject is randomized and starts receiving study drugs Subject will return at weeks 2, 4, 8, 12, 16, 24, 32, 40 and 48 and the following will be done: Vitals Symptom directed physical exam Adverse Events and Concomitant Medications assessments Blood draws – actual tests will differ depending on the visitFollow-up post study drug phaseFollow-up post study drug phaseSubject will return for follow-up weeks 52 and 60 and the following will be done: Vitals Symptom directed physical exam Adverse Events and Concomitant Medications assessments Blood draws – actual tests will differ depending on the visitLiver Biopsy and Histology DefinitionsLiver Biopsy and Histology DefinitionsA new liver biopsy at the screening visit will not be necessary in the event that a subject has had a previous liver biopsy taken within 12 months of the baseline Blood samples for biomarkers and banking Serum samples for FibroTest/ActiTest (Fibrosure) The central histopathologist will also perform collagen morphometry analysis & immunohistochemical staining (i.e., α-SMA) on the biopsy slidesBiomarkers for Hepatic FibrosisBiomarkers for Hepatic FibrosisHCV FibroSure: A commercially available laboratory test Comprised of the FibroTest and the ActiTest will be performed at Referance lab. Fibrotest combines the blood measurement of five indirect markers of fibrosis (alpha2-macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, and gamma glutamyl transpeptidase), adjusted for age and sex. The activity index (ActiTest) combines the same markers along with the measurement of ALT. This panel will be assayed at screening, baseline, and at Weeks 4, 12, 24, 36, 48 and at week 4, 8 and 12 of follow-up. Biomarkers for Hepatic Fibrosis continuedBiomarkers for Hepatic Fibrosis continuedCandidate serum proteins: Identified based upon the underlying disease biology include those related to extracellular matrix deposition and breakdown, proteins involved in signaling pathways which may regulate hepatic stellate cells (HSC), and proteins involved in hepatic inflammation. These proteins will be measured using a validated multiplex assay at a Reference lab Will measure at screening, baseline, and at Weeks 4, 16, 28, 40, 48 and the 12 week follow-up. VirologyVirologySerum for determination of HCV genotype will be collected if the genotype is not known Serum for HCV RNA levels will be collected at screening, baseline, Week 24, Week 48, and at the 12 week follow-up visit. Primary EndpointsPrimary EndpointsEfficacy: Proportion of subjects regressing at least 1 point on the Ishak fibrosis score at Week 48 on each arm of the study Change from baseline in fibrosis stage (quantified by morphometric image analysis) Ranked histological assessment of the paired biopsies (Baseline versus Week 48) Safety: Assessment of safety and tolerability of Fuzhenghuayu in comparison with placebo in respect to adverse events Nature and frequency of adverse events and laboratory abnormalities Changes over time in laboratory parameters and vital signs Changes in QOL and cognitive parameters between the 2 groupsSecondary EndpointsSecondary EndpointsChange from baseline in liver biopsy fibrosis stage (Ishak score) and by immunohistochemical markers of HSC activation and collagen synthesis Proportion of subjects whose Ishak fibrosis score remains unchanged at Week 48 on each arm of the study Change from baseline in total Ishak Score (necroinflammatory score and fibrosis score) at Week 48 Change from baseline in Metavir scores Change from baseline in serum ALT levels Change from baseline in serum HCV RNA levels Percentage of subjects with >1log change in serum HCV RNA over 48 weeks Changes in % steatosis from base line* Progression is defined as an increase of at least one point in the fibrosis score Efficacy AnalysisEfficacy AnalysisHistological assessments The screening and Week 48 biopsy slides will be evaluated for efficacy endpoint assessments Will be scored according to Ishak and Metavir Scores Will be read by a central histopathologist Change from baseline in liver biopsy immunohistochemical markers of HSC activation and collagen synthesis Change in fibrosis as quantified by morphometric image analysis Ranked assessment of paired biopsies (Baseline vs. Week >48) Safety AnalysisSafety AnalysisThe timing of Safety assessments follows the standard procedure for assessing safety and will be examined by: Adverse events and concomitant medications Various laboratory assessments An Independent DSMBAssessment of ComplianceAssessment of ComplianceThe necessity for study drug compliance will be reinforced with the study subject at each study visit. Compliance with study medication will be evaluated using pill counts of unused study medication (Fuzhenghuayu or placebo). Statistical AnalysisStatistical AnalysisAll treatment comparisons will be performed on the ITT population. No interim analysis will be performed If scores do not violate the assumption of homogeneity of variance, repeated measures multivariate analyses of variance (MANOVAs) will be conducted. If significant differences are found, follow-up ANOVAs and Tukey’s LSD post-hoc analyses will be performed to identify the specific scores found to differ significantly. If scores are found to violate the assumption of homogeneity of variance, appropriate nonparametric analyses will be utilized.* Statistical analysis will be done at the Shanghai University of TCM under the direction of Professor Leal Administrative AspectsAdministrative AspectsAdhere to regulatoray and ethical guidelines Adhere to Good Clinical Practices Perform quality controls and assurances by independent monitorsConclusion: FZHY for Liver FibrosisConclusion: FZHY for Liver FibrosisFZHY is an antifibrotic with good safety profile. Efforts are underway to explore its clinical efficacy in ameliorating liver fibrosis in HCV infected patients The successful completion of the Clinical Trial of FuzhengHuayu as an antifibrogenic will open the door for more collaborations and applications of TCM in complementing Western Medicine.FZHY Study: MilestonesFZHY Study: MilestonesProtocol Development: March 2006 Protocol Discussion: October 2006 FDA IND application: November 2006 FDA approval: December 2006 IRB submission: April 2009 IRB approval: July 2009 Contract execution: August 2009 Randomization of first patient: August 2010Study CentersStudy CentersSCTI Research Foundation, San Diego (T.Hassanein) University of California, Davis (L. Rozzaro) (A hammadian) Southern California Liver Centers (R. Pozza) Huntington Memorial Liver Res. Center (M. Tong) University of Illinois (S. Cottler) University of Utah (T. Box) Baylor College of Medicine (J. Vierling) Stanford University (J. Glenn) Study Update April 20, 2011Study Update April 20, 2011First subject screened: June 30, 2010 First subject randomized: August 4, 2010 26 subjects are past week 12 13 subjects are past week 24 Randomization Distribution: Aug: 1 – Jan: 3 Sep: 4 – Feb: 13 Oct: 10 – Mar: 11 Nov: 6 – Apr: 4 Dec: 4