Chinese Herbal Medicine Combined with Entecavir for HBeAg Positive Chronic Hepatitis B:Study Protocol for a Multi-Center,Double-Blind Randomized-Controlled Trial

Background： The domestic prevalence of chronic hepatitis B （CHB） in China is 7.18% in 2006, imposing great societal healthcare burdens. Nucleot（s）ide analogues （NUCs） anti-hepatitis B virus （HBV） therapies are widely applied despite the relatively low rate of seroconversion and high risk of drug-resistant mutation. More effective treatments for CHB deserve further explorations. Combined therapy of NUCs plus Chinese herbal medicine （CHM） is widely accepted in China, which is recognized as a prospective alternative approach. The study was primarily designed to confirm the hypothesis that Tiaogan-Yipi Granule （调肝益脾颗粒, TGYP） or Tiaogan-Jianpi-Jiedu Granule （调肝健脾解毒颗粒, TGJPJD） plus entecavir tablet （ETV） was superior over ETV monotherapy in enhancing HBeAg loss rate. Methods： The study was a nationwide, large-scale, multi-center, double-blind, randomized, placebo-controlled trial with a designed duration of 108 weeks. A total of 16 hospitals and 596 eligible Chinese HBeAg positive CHB patients were enrolled from November 2012 to September 2013 and randomly allocated into 2 groups in 1：1 ratio via central randomization system： experimental group （EG） and control group （CG）. Subjects in EG received CM formulae （TGYP or TGJPJD, 50 g per dose, twice daily） plus ETV tablet （or ETV placebo） 0.5 mg per day in the first 24 weeks （stage 1）, and CHM granule plus ETV tablet （0.5 mg per day） from week 25 to 108 （stage 2）. Subjects in CG received CHM Granule placebo plus E＇IV tablet （0.5 mg per day） for 108 weeks throughout the trial. The assessments of primary outcomes （HBV serum markers and HBV-DNA） were conducted by a third-party College of American Pathologists （CAP） qualified laboratory. Adverse effects were observed in the hospitals of recruitment. Discussion： The study was designed to compare the curative effect of CM plus E＇IV and ETV monotherapy in respect of HBeAg loss, which is recognized by the European Association for the Study of the Liver as ＂a valuable endpoint＂. We believe this trial could provide a reliable status for patients＇ ＂joumey＂ towards durable responses after treatment discontinuation. The trial was registered before recruitment on Chinese Clinical trial registry （No. ChiCTR-TRC-12002784, Version 1.0, 2015/12/23）.

Improvement cues of lesion absorption using the adjuvant therapy of traditional Chinese medicine Qinbudan tablet for retreatment pulmonary tuberculosis with standard anti-tuberculosis regimen

Background:China is the second highest pulmonary tuberculosis(PTB)burden country worldwide.However,retreatment of PTB has often developed resistance to at least one of the four first-line anti-TB drugs.The cure rate(approximately 50.0–73.3%)and management of retreatment of PTB in China needs to be improved.Qinbudan decoction has been widely used to treat PTB in China since the 1960s.Previously clinical studies have shown that the Qinbudan tablet(QBDT)promoted sputum-culture negative conversion and lesion absorption.However,powerful evidence from a randomized controlled clinical trial is lacking.Therefore,the aim of this study was to compare the efficacy and safety of QBDT as an adjunct therapy for retreatment of PTB.Methods:We conducted a multicenter,randomized,double-blind,placebo-controlled clinical trial in China.People diagnosed with PTB were enrolled who received previous anti-TB treatment from April 2011 to March 2013.The treatment group received an anti-TB regimen and QBDT,and the control group was administered an anti-TB regimen plus placebo.Anti-TB treatment options included isoniazid,rifampicin,pyrazinamide,ethambutol,streptomycin for 2 months(2HRZES),followed by isoniazid,rifampicin,ethambutol for 6 months(6HRE),daily for 8 months.Primary outcome was sputum-culture conversion using the MGIT 960 liquid medium method.Secondary outcomes included lung lesion absorption and cavity closure.Adverse events and reactions were observed after treatment.A structured questionnaire was used to record demographic information and clinical symptoms of all subjects.Data analysis was performed by SPSS 25.0 software in the full analysis set(FAS)population.Results:One hundred eighty-one cases of retreatment PTB were randomly divided into two groups:the placebo group(88 cases)and the QBDT group(93 cases).A total of 166 patients completed the trial and 15 patients lost to follow-up.The culture conversion rate of the QBDT group and placebo group did not show a noticeable improvement by using the covariate sites to correct the rate differences(79.6%vs 69.3%;rate difference=0.10,95%confidence interval(CI):-0.02–0.23;F=2.48,P=0.12)after treatment.A significant 16.6%increase in lesion absorption was observed in the QBDT group when compared with the placebo group(67.7%vs 51.1%;rate difference=0.17,95%CI:0.02–0.31;χ2=5.56,P=0.02).The intervention and placebo group did not differ in terms of cavity closure(25.5%vs 21.1%;rate difference=0.04,95%CI:-0.21–0.12;χ2=0.27,P=0.60).Two patients who received chemotherapy and combined QBDT reported pruritus/nausea and vomiting.Conclusions:No significant improvement in culture conversion was observed for retreatment PTB with traditional Chinese medicine plus standard anti-TB regimen.However,QBDT as an adjunct therapy significantly promoted lesion absorption,thereby reducing lung injury due to Mycobacterium tuberculosis infection.Trial registration:This trial is registered at ClinicalTrials.gov,NCT02313610.

Botanical drug clinical trial: Common issues and future options

In order to understand this disparity between human use and drugs approved by regulatory agencies,we analyzed botanical drug clinical trials registered at ClinicalTrial.gov to detect trends in current trials and guide future trials.A total of 195 botanical drug clinical trials were registered from 2016 to2019,of which 81 are phaseⅡor phaseⅡ/Ⅲ.95%of all phaseⅡandⅡ/Ⅲstudies were designed with100 or less participants per arm,indicating a more observational nature due to the limited power to detect differences in outcomes between treatment and control groups.Due to the limited number of participants,efficacy outcome from results may be highly subjective.14%of the total trials were phaseⅠstudies.For botanical drugs with well-documented or extensive history of human use,phaseⅠmay not provide significant additional information,and may,therefore,not be necessary.For the trial design,we suggest added-on studies when botanical drugs are used as part of a combination treatment.Additionally,we believe standardized data collection methods and criteria are critical to utilizing the vast collection of human experience as quality evidence to support regulatory approval.