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Placebo design in WHO-registered trials of Chinese herbal medicine need improvements.

ABSTRACT: BACKGROUND:Physical identical and pharmacological inert are the basic requirements for placebo design, which are essential in clinical trials to evaluate the efficacy of an intervention. However, it is difficult to makeup a placebo of Chinese herbal medicine (CHM) because of special color, taste and smell, etc. Currently, there is no specific requirements and standards for the creation of a CHM-placebo. The purpose of this study is to review the characteristics of the CHM-placebo design and application in registered clinical trials with CHM interventions and identify the common problems, if any. METHODS:The World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) was systematically searched for CHM interventional trials with placebo-controlled design up to 31 December 2017. Registered information of each included trial was collected from specific registries involved in ICTRP through hyperlinks. Descriptive statistics were used to analyze the characteristics of placebo design in CHM trial registrations. RESULTS:A total of 889 CHM interventional trials were registered from 1999 to 2017, and 40.8% (363) of them included CHM-placebo control design. The common ways of their design were: placebo as sole control (191, 52.6%); placebo as add-on control with baseline treatment (84, 23.1%); and placebo as double-dummy control (57, 15.7%). Among 363 included trials, 46 (12.7%) reported the compositions of placebos, including CHM ingredients (17 trials), excipients and other agents (29 trials). 2 (0.6%) reported pharmacological inert testing, and 52 (14.3%) descripted their placebos to be physically identical with the CHMs. 14 (3.9%) reported quality control of placebos, and 2 (0.6%) provided blinding assessment of placebos. CONCLUSIONS:The placebos included in most CHM trial registrations is not optimal in terms of placebo design, application, evaluation and reporting. Specific guidelines or standards of CHM-placebo design, including usage requirements, preparation specifications, quality assessments and reporting guidelines should be developed thus to improve their quality.

SUBMITTER: Zhang X

PROVIDER: S-EPMC6836479 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Placebo design in WHO-registered trials of Chinese herbal medicine need improvements.

Zhang Xuan X Tian Ran R Zhao Chen C Tang Xudong X Lu Aiping A Bian Zhaoxiang Z

BMC complementary and alternative medicine 20191106 1

<h4>Background</h4>Physical identical and pharmacological inert are the basic requirements for placebo design, which are essential in clinical trials to evaluate the efficacy of an intervention. However, it is difficult to makeup a placebo of Chinese herbal medicine (CHM) because of special color, taste and smell, etc. Currently, there is no specific requirements and standards for the creation of a CHM-placebo. The purpose of this study is to review the characteristics of the CHM-placebo design ...[more]

PMID: 31694626

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Project description:ObjectivesTo provide a broad evaluation of the efficacy and safety of oral Chinese herbal medicine (CHM) as an adjunctive treatment for diabetic kidney disease (DKD), including mortality, progression to end-stage kidney disease (ESKD), albuminuria, proteinuria and kidney function.DesignA systematic review and meta-analysis.MethodsRandomised controlled trials (RCTs) comparing oral CHM with placebo as an additional intervention to conventional treatments were retrieved from five English (Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Allied and Complementary Medicine Database and Cumulative Index of Nursing and Allied Health Literature) and four Chinese databases (China BioMedical Literature, China National Knowledge Infrastructure, Chonqing VIP and Wanfang) from inception to May 2018. RCTs recruiting adult DKD patients induced by primary diabetes were considered eligible, regardless of the form and ingredients of oral CHM. Mean difference (MD) or standardised mean difference (SMD) was used to analyse continuous variables and RR for dichotomous data.ResultsFrom 7255 reports retrieved, 20 eligible studies involving 2719 DKD patients were included. CHM was associated with greater reduction of albuminuria than placebo, regardless of whether renin-angiotensin system (RAS) inhibitors were concurrently administered (SMD -0.56, 95% CI [-1.04 to -0.08], I2=64%, p=0.002) or not (SMD -0.92, 95% CI [-1.35 to -0.51], I2=87%, p<0.0001). When CHM was used as an adjunct to RAS inhibitors, estimated glomerular filtration rate was higher in the CHM than placebo group (MD 6.28 mL/min; 95% CI [2.42 to 10.14], I2=0%, p=0.001). The effects of CHM on progression to ESKD and mortality were uncertain due to low event rates. The reported adverse events in CHM group included digestive disorders, elevated liver enzyme level, infection, anaemia, hypertension and subarachnoid haemorrhage, but the report rates were low and similar to control groups. The favourable results of CHM should be balanced with the limitations of the included studies such as high heterogeneity, short follow-up periods, small numbers of clinical events and older patients with less advanced disease.ConclusionsBased on moderate to low quality evidence, CHM may have beneficial effects on renal function and albuminuria beyond that afforded by conventional treatment in adults with DKD. Further well-conducted, adequately powered trials with representative DKD populations are warranted to confirm the long-term effect of CHM, particularly on clinically relevant outcomes.Prospero registration numberCRD42015029293.

Project description:Background: Chinese herbal medicine (CHM) provides a theoretical basis for the treatment of psoriasis with considerable benefits and a low toxicity. The purpose of this quantitative study was to show high-quality evidence of the efficacy and safety of CHM for the treatment of psoriasis to promote its clinical application. Methods: Several databases were systematically searched including PubMed, Embase, Cochrane Central Register of Controlled Trials, China Network Knowledge Infrastructure, Chinese Scientific Journals Database, and Wan Fang Database. High-quality randomized controlled trials that compared CHM with non-CHM interventions were included. The RevMan5.3 software was used to calculate risk ratios (RR) at 95% confidence intervals (CI) and conduct the meta-analysis. Results: Altogether, 1,215 patients participated in this study, including 711 in the experimental group and 504 in the control group. The psoriasis area severity index (PASI) score of the CHM group was significantly lower than that of the placebo group (MD, -4.02; 95% CI, -6.71 to -1.34; p = 0.003). To achieve PASI-60 and PASI-75, the arrival rate of the CHM group was higher than that of the placebo group (PASI-60: RR, 3.52; 95% CI, 1.17 to 10.61; p = 0.03; PASI-75: RR, 9.87; 95% CI, 3.11 to 31.31; p = 0.0001). Furthermore, the efficacy rate was higher in patients receiving CHM than in those receiving placebo (RR, 1.72; 95% CI, 1.01 to 2.93; p = 0.04). The results suggested a greater impact of CHM in improving the dermatology life quality index (DLQI) of patients (MD, -2.12; 95% CI, -3.75 to -0.49; p = 0.01). Regarding pruritus severity, there was no significant difference between the two groups (MD, -1.90; 95% CI, -3.79 to -0.01; p = 0.05). The meta-analysis revealed that the recurrence rate (RR, 0.74; 95% CI, 0.32 to 1.71; p = 0.48) and proportion of adverse events (RR, 1.36; 95% CI, 0.95 to 1.93; p = 0.09) associated with using CHM were similar to those associated with using a placebo. Conclusion: CHM appears safe and effective in the treatment of psoriasis and has a great positive impact on the DQLI of patients; however, CHM could not completely eliminate skin lesions, improve pruritus severity, and reduce the recurrence rate.

Project description:BackgroundMultiple primary outcomes are commonly used in randomized controlled trials (RCTs) of Chinese herbal medicine (CHM). Analysis and interpretation of the results of CHM RCTs with many outcomes are not clear. No previous studies have systematically assessed the use of multiple primary outcomes in this area. This study aimed to assess the reporting of multiple primary outcomes and the statistical methods used to adjust multiplicity in RCTs of CHM.MethodsSearch for RCTs of CHM published in English between January 2010 and December 2019 in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) was undertaken. We randomly selected 20% of the included RCTs as the analyzing sample of this study. The number of multiple primary outcomes, the methods used to adjust the multiplicity in statistical analysis and sample size estimate, and the trial information were collected. For RCTs that adopted multiple primary outcomes without the multiplicity adjustment, we used Bonferroni correction to adjust.Results227 CHM RCTs were included in our study. 92 (40.5%) failed to report what their primary outcome was. Of 135 (59.5%) RCTs that reported primary outcome, 93 (68.9%) reported one and 42 (31.1%) reported more than one primary outcome (range 2-5). Of 42 RCTs that reported multiple primary outcomes, only 5 adjusted for multiple outcomes. If multiplicity had been accounted for using Bonferroni correction, 10 (37.0%) RCTs that reported a significant result had demonstrated a nonsignificant result, giving the adjusted P value. Only one of the 42 RCTs calculated sample size based on multiple primary outcomes. Adopting multiple primary outcomes showed a slow growth trend with the publication year. The proportion of primary outcome reported explicitly in RCTs was different in terms of the nationality of the first author (P=0.004), in which mainland China has the lowest proportion (55.8%). The highest percentage of the studies with primary outcome reporting explicitation was mental and behavioural disorders (83.3%), and the most frequently adopting multiple primary outcomes were studies on the disease of the nervous system (66.7%). The percentage of reporting primary outcome explicitly was associated with sample size (P < 0.001); for the percentage of RCTs adopting multiple primary outcomes, there was no statistically significant difference (P=0.739).ConclusionsMultiple primary outcomes are prevalent in CHM RCTs. However, appropriate methods are not usually taken in most of the analyses to safeguard the inferences against multiplicity. Sample size estimation based on multiple primary outcomes is still lacking. These issues complicate the interpretability of trial results and can lead to spurious conclusions. Guidelines to improve analyzing and reporting for multiple primary outcomes in CHM RCTs are warranted.

Project description:PurposeAcute exacerbation of chronic obstructive pulmonary disease (AECOPD) is an essential occurrence in COPD management and is the leading cause of morbidity and mortality. Chinese herbal medicine is widely used in the treatment of AECOPD, but high quality randomized controlled trials are limited. This study aimed to evaluate the efficacy and safety of Chinese herbal medicine as adjuvant therapy for patients with AECOPD.MethodsThis was a randomized, double-blind, placebo-controlled study of 378 participants from eight centers in China. Participants were randomly assigned to receive 10 g of Chinese herbal medicine (according to the type of Traditional Chinese medicine syndrome: Sanhanhuayin, Qingrehuatan, or Zaoshihuatan granules) or placebo, two times per day, for 14 days, in addition to conventional medicine. Participants were followed up for 84 days after the treatment. The primary end point was the COPD assessment test (CAT) score. Secondary end points included the Modified British Medical Research Council (mMRC) questionnaire and the COPD patient-reported outcome scale (COPD-PRO). We also assessed treatment failure and treatment success rate, length of hospitalization, number of patients with acute exacerbations, number of patients readmitted due to AECOPD, and number of deaths and intubation.ResultsThe between-group difference in the change from baseline for CAT on day 14 (end of treatment) was -2.11 (95% confidence interval [CI], -3.198 to -1.050; P<0.001), exceeding the minimal clinically important difference. The mMRC and COPD-PRO scores were lower in the intervention group compared to the control group (between-group difference in the change from baseline, -0.28; 95% CI, -0.48 to -0.08; P=0.007 and -2.51; 95% CI, -4.087 to -0.929; P=0.002, respectively) on day 14. The intervention group had a significantly shorter duration of hospital stay than the control group (mean difference, -1.21days; 95% CI, -2.041 to -0.419; P=0.003), significantly lower of number of exacerbations (risk ratio [RR], 0.60; 95% CI, 0.409 to 0.892; P=0.010), and significantly lower number of readmissions due to AECOPD (RR, 0.41; 95% CI, 0.193 to 0.865; P=0.015). Significant differences in the number of treatment failures or successes, deaths, and intubation were not observed. The difference in safety variables and adverse events between the two groups was not observed.ConclusionChinese herbal medicine appears to be safe and beneficial for AECOPD and can be considered a complementary treatment for patients with AECOPD.

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Placebo design in WHO-registered trials of Chinese herbal medicine need improvements.

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Placebo design in WHO-registered trials of Chinese herbal medicine need improvements.

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