肠安Ⅰ号方治疗IBS-D的临床疗效评价暨临床疗效评价指标的比较研究
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摘要
研究主要分为三个部分,分别为中药汤剂安慰剂的制作探讨、肠安Ⅰ号方治疗腹泻型肠易激综合征(IBS-D)的临床疗效评价研究和中医药治疗肠易激综合征(IBS)临床疗效评价指标的比较研究。
1中药汤剂安慰剂的制作探讨
目的：中药汤剂安慰剂制作的理论与实践均不成熟,本研究探讨中药汤剂肠安Ⅰ号方安慰剂的制作方法,为中药汤剂的双盲安慰剂对照临床试验提供技术支持。
方法：经过多次试验,最终采取以大米(炒至焦黄色)为辅料,配合5%原药煎制而成。
结果：(1)通过视觉模拟量表,对安慰剂的外观、口味及中药汤剂模拟效果进行评价。结果表明,肠安Ⅰ号方原药在外观、口味、中药汤剂模拟效果方面的得分分别为9.10±0.60、9.00±0.60、9.30±0.70。安慰剂的得分分别为8.20±1.30、7.40±0.90、9.10±0.70；两者比较,在外观方面无统计学差异(p>0.05)；在口味方面,两者比较,有统计学差异(p<0.05)。但在中药汤剂模拟效果评测的判定中,两者无统计学差异,均符合常人对中药的认知。(2)实验研究表明,肠安Ⅰ号方安慰剂对实验大鼠的内脏高敏感性、胃肠动力没有作用,没有镇痛及抗炎的作用。
结论：肠安Ⅰ号方安慰剂符合常人对中药汤剂的认知,外观与肠安Ⅰ号方相似,且无明显药理作用,可以作为安慰剂使用。
2肠安Ⅰ号方治疗IBS-D的临床疗效评价研究
目的：中药汤剂是中医药临床治疗IBS-D的主要剂型,目前尚未有使用中药汤剂治疗IBS-D的随机、双盲、安慰剂对照的临床试验报道。本研究采用规范的临床试验设计方法和公认的临床疗效评价指标,评价中药汤剂肠安Ⅰ号方治疗IBS-D的临床疗效及安全性。
方法：采用随机、双盲、安慰剂对照临床试验设计,对符合纳入标准,不符合排除标准IBS-D患者,由药品管理员按照入组顺序,根据随机信封的药物编码,制作并发放相应的研究药物。试验组予以肠安Ⅰ号方,150ml/袋,3/日；对照组予以安慰剂,150ml/袋,3/日,疗程均为8周。
结果：共纳入患者60例,试验组与对照组各30例,纳入全分析集(FAS)分析58例；纳入符合方案集(PP)分析56例。主要疗效评价指标包括IBS症状严重程度量表(IBS-SSS)的积分变化、明显缓解(AR)应答(Responder)的差异；次要疗效指标包括IBS-SSS的等级改善、IBS生活质量量表(IBS-QOL)的总积分及各个维度积分变化、医院焦虑与抑郁量表(HAD)焦虑子量表与抑郁子量表的积分变化、中医相关症状总积分及中医证型相关症状积分变化、排便相关症状改善；安全性指标包括不良事件及相关实验室检查。
(1)主要疗效指标：
1) IBS-SSS量表积分改善。FAS：试验组在基线期、用药后第2周、第4周、第6周、第8周的积分分别为242.52±69.84、213.56±93.4、198.83±92.45、169.04±92.31、125.30±78.94；对照组为265.39±97.92、214.63±84.37、212.29±91.93、209.73±107.54、194.01±96.53,经比较,两组间差异有统计学意义(P<0.05)。PP：试验组在基线期、用药后第2周、第4周、第6周、第8周的积分分别为242.52±69.84、213.56±93.4、198.83±92.45、169.04±92.31、125.30±78.94；对照组为260.28±99.45、210.36±83.8、210.81±87.82、204.43±104.82、188.05±91.34,经比较,两组间的差异有统计学意义(p<0.05)。FAS与PP的结论一致,试验组的疗效优于对照组。
2)AR应答。FAS：试验组有应答者25(89.3%)人,无应答者3(10.7%)人；对照组有应答者11(36.7%)人,无应答者19(63.3%)人；经比较,两组间差异有统计学意义(p<0.05)。PP：试验组有应答者25(89.3%)人,无应答者3(10.7%)人；对照组有应答者11(39.3%)人,无应答者17(60.7%)人；经比较,两组间差异有统计学意义p<0.05)。FAS与PP结论一致,试验组疗效优于对照组。
(2)次要疗效指标
1) IBS-SSS等级改善。试验组痊愈者9例,显效者1例,有效者7例,无效者11例；对照组痊愈者3例,显效者2例,有效者11例,无效者14例,经Ridit检验,两组间差异无统计学意义(p>0.05)。
2) IBS-QOL改善。IBS-QOL总积分：试验组在基线、用药后第4周、第8周积分分别为31.75±21.19、28.52±20.42、23.82±21.52；对照组分别为38.75±24.90、28.11±19.46、29.14±22.61。心境恶劣维度积分：试验组分别为35.83±27.05、30.69±24.62、23.33±26.03；对照组分别为45.21±27.75、31.15±20.72、34.06±27.70。行为障碍维度积分：试验组分别为37.76±25.13、32.78±23.75、29.72±25.64；对照组分别为42.62±31.15、32.26±24.25、33.33±25.38。自体意象维度积分：试验组分别为16.07±20.58、17.41±22.59、16.29±19.49；对照组分别为25.42±27.12、18.13±21.23、21.25±23.65。健康担忧维度积分：试验组分别为47.02±30.36、36.90±27.82、29.46±29.44；对照组分别为51.11±25.78、34.72±22.00、30.00±21.06。进食逃避维度积分：试验组分别为44.35±29.14、44.94±28.63、38.10±29.35；对照组分别为47.22±33.36、40.56±25.96、43.06±27.78。社会功能维度积分：试验组分别为22.99±20.42、20.83±18.91、18.08±21.87；对照组分别为28.75±25.09、19.58±18.18、22.08±21.19。性行为维度积分：试验组分别为18.75±19.98、18.75±20.27、13.84±22.91；对照组分别为33.75±37.16、18.33±27.41、17.92±25.99。关系拓展维度积分：试验组分别为20.24±21.57、18.45±19.43、15.77±18.33；对照组分别为26.11±26.87、19.72±22.15、18.89±23.05。经比较,IBS-QOL总积分及各个维度积分在两组间均无统计学差异(p>0.05)。
3)HAD积分。焦虑子量表积分：试验组在基线、用药后第4周、第8周积分分别为8.07±4.01、7.68±3.99、7.07±4.09；对照组分别为8.03±4.06、7.63±3.21、6.87±3.88；经比较,两组间差异无统计学意义(p>0.05)。抑郁子量表积分：试验组在基线、用药后第4周、第8周积分分别为7.96±2.92、8.04±3.02、7.96±3.31；对照组分别为8.37±3.65、7.80±3.08、7.27±3.52；经比较,两组间差异无统计学意义(p>0.05)。
4)中医症状积分。试验组在基线、用药后第4周、第8周中医症状总积分分别为24.75±7.53、20.75±8.93、16.82±8.12；对照组分别为22.67±9.02、19.07±9.80、19.17±9.66；经比较,两组间差异无统计学意义(p>0.05)。但试验组对中医症状总积分及肝脾不和型、脾胃虚弱型、脾肾阳虚型相关症状的改善趋势比对照组更为明显。
5)排便相关症状。试验组在腹痛指数、排便指数、性状指数、便急指数、感觉指数和粘液指数方面与对照组相比,差异均无统计学意义(p>0.05)。试验组在腹痛指数、排便指数、性状指数、便急指数、感觉指数、粘液指数方面均呈明显下降趋势；对照组在腹痛指数、性状指数、便急指数、粘液指数也呈下降趋势；但趋势不如试验组明显。
(3)安全性检查
研究中未发现明确与临床试验药物相关的、有临床意义的不良事件和实验室检查异常。
结论：肠安Ⅰ号方治疗IBS-D临床能够明显降低IBS-SSS积分,提高AR应答率,疗效优于安慰剂,临床未发现明确不良反应。表明肠安Ⅰ号方治疗IBS-D是临床有效安全的。次要疗效指标未能显示出统计学差异,考虑与指标本身的反应度低及临床研究的样本量不足相关,宜扩大样本量进一步研究。
3中医药治疗IBS的临床疗效评价指标比较研究
目的：我国IBS中医药临床疗效评价多采取复合指标评价的方式,与国外通行的疗效评价方式有一定的差距,罗马Ⅲ标准对IBS的临床疗效评价指标提出了推荐意见,但由于缺乏实际的数据支持而面临一定的争议。本研究以临床试验为依托,考察IBS临床研究中常用疗效评价指标的反应度,为IBS相关中医药临床试验的临床疗效评价指标的使用提供参考。
方法：以“排便相关症状”为有意义的临床变化,分别考察IBS-SSS、AR、IBS-QOL、HAD与排便相关症状的关系及其临床反应度。
结果：(1)IBS-SSS与排便相关症状、焦虑状态存在线性相关关系,其效应尺度为1.59,临床反应度较高。(2)AR的单次应答与排便相关症状存在线性相关关系。(3) IBS-QOL与排便相关症状线性相关关系不明显,与焦虑状态有一定的关联,效应尺度为0.61,具有中等反应度。(4)HAD中焦虑子量表、抑郁子量表积分与排状相关症状不存在线性相关关系,焦虑子量表的效应尺度为0.34,抑郁子量表的效应尺度为0.03,临床反应度较低。
结论：IBS-SSS临床反应度较好,与排便相关症状及焦虑状态明确相关,适合在临床疗效评价中使用；AR的单次应答与症状相关,由于在临床疗效评价过程中,常将多次应答组合成复合评价指标,因此需注意其“有临床意义”的界定；IBS-QOL与焦虑状态相关,与症状关系不明确,具有中等临床反应度,适合观察周期较长的临床研究使用；HAD临床反应度较低,不适合作为临床疗效评价指标使用。
There are three parts in this research, including manufacturing of placebo of Chang'anyihao Decoction, the clinical research of Chang' anyihao Decoction in treat-ing irritable bowel syndrome with diarrhea (IBS-D) and research of responsibility of common irritable bowel syndrome (IBS) clinical effect assessment indices.
1 Manufacturing of placebo of Chang'anyihao Decoction
Objective The lack of related theory and practical use of placebo in TCM decoction prevented higher quality of responding clinical trials. We exploited the manufacturing methods of placebo of Chang'anyihao Decoction to provide support for a dou-ble-blind, placebo-controlled trial of TCM decoction.
Methods We finally took stir-frying rice as the main excipients, and accompanied by 5% of Chang' anyihao Decoction to manufacture the placebo after several pilot trials.
Results (1) Visual analogue scales (VAS) was adopt to evaluate the appearance, taste and similarity to common TCM decoction. The score of appearance, taste and similar-ity to TCM decoction was 9.10±0.60、9.00±0.60、9.30±0.70 in Chang'anyihao De-coction, and of which in placebo was 8.20±1.30、7.40±0.90、9.10±0.70. Although there were significant differences in taste between two groups (p<0.05), there were no statistically significant differences between two drugs in appearance and similarity to TCM decoction (p>0.05). (2)Experiments also proved that the placebo exerted no ef-fect in visceral hypersensitivity, gastrointestinal motility and inflammation condition.
Conclusions Placebo of Chang'anyihao Decoction accorded with common sense and recognition of TCM decoction of ordinary people, and it can be taken as placebo for its similar appearance and pharmacological ineffective.
2 Clinical research of Chang'anyihao Decoction in treating IBS-D
Objective Decoction was the main preparation in the treatment of IBS-D in TCM practice, while there were no substantial evidences to prove the effectiveness of TCM decoction. We performed a clinical trial to evaluate the effectiveness and safety of Chang'anyihao Decoction.
Methods A randomized, double-blinded, placebo-controlled clinical trial design was adopted in the trial. Patients were given responding drugs by the drug administrator according to their inclusion sequences. The experiment group was given Chang'anyihao Decoction150ml three times a day, and the control group was given placebo 150ml three times a day. The treatment courses of both groups were 8 weeks.
Results Among 60 included patients,58 were screened for full analysis set (FAS), and 56 were screened per-protocol set (PPS). The results were as follows:
(1) Primary outcomes
1) Improvement of irritable bowel syndrome symptom severity score (IBS-SSS). In FAS, the score were 242.52±69.84、213.56±93.4、198.83±92.45、169.04±92.31、125.30±78.94 in baseline,2 weeks after treatment,4 weeks after treatment,6 weeks after treatment and 8 weeks after treatment in experiment group, and in control group, the score were 265.39±97.92、214.63±84.37、212.29±91.93、209.73±107.54、194.01±96.53 respectively. In PP, the score were 242.52±69.84、213.56±93.4、198.83±92.45、169.04±92.31、125.30±78.94 from baseline to 8 weeks after treatment in experiment group, and in control group, the score were 260.28±99.45、210.36±83.8、210.81±87.82、204.43±104.82、188.05±91.34 respectively. The differences were statistically significant between the two groups (p<0.05), FAS and PP had the same results.
2) Comparison of adequate relief (AR). In FAS, the responder rate was 89.3%(25/28) in experiment group and the rate is 36.7%(11/30) in control group. In PP, the re-sponder rate was 89.3%(25/28) and 39.3%(11/28) respectively. The differences were statistically significant between the two groups (p<0.05), FAS and PP had the same results.
(2) Secondary outcomes
Secondary outcomes included the ranked improvement of IBS-SSS, change in irrita-ble bowel syndrome- quality of life questionnaire (IBS-QOL) total score and subscale score, score change in hospital anxiety and depression scale (HAD), TCM symptoms and defecation related symptoms. To all secondary outcomes, there were no statisti-cally significant differences between the two groups (p>0.05). But to TCM symptoms and its subtype symptoms, and the symptoms indices of defecation related symptoms, the experiment group manifested a better tendency in improvement.
(3) Assessment of safety
There were no specific adverse events and laboratory test concerned to research drugs happened.
Conclusions Chang'anyihao was effective and safe in clinical practice with a definite improvement in IBS-SSS score, a higher AR responder rate, and less adverse reaction.
3 Research of responsibility of common IBS clinical effect assessment indices
Objective Rome III proposed suggestions of clinical effect assessment indices for IBS clinical trials according to literature, while the suggestions lacked valid data support and in China, researches of these suggested indices were even less. We conducted the research to evaluate the responsibility of each common index for further IBS clinical trial use.
Methods Indices of IBS-SSS, AR, IBS-QOL, HAD were appraised taken defecation related symptoms as clinical meaningful references.
Results (1) The score of IBS-SSS had a linear regression with defecation related symptoms and anxiety score, the responsibility was high with an effect size of 1.59. (2) Response to each AR response was related to defecation related symptoms. (3) The score of IBS-QOL did not correlate with defecation related symptoms, but had a rela-tionship with anxiety with an effect size of 0.61. (4) Anxiety and depression score measured by HAD had no relationship with defecation related symptoms and the ef-fect size was low.
Conclusions IBS-SSS was a good tool for IBS clinical trials for its high responsibility and relation with defecation related symptoms. AR singly assessment reflected the clinical symptoms change, for it always been changed for a kind of complex assess-ment indices, attention should be paid to the clinical meaning. IBS-QOL may be used for long term research for it was insensitive to short term clinical changes. HAD was improper for IBS clinical effect evaluation.
1中药汤剂安慰剂的制作探讨
目的：中药汤剂安慰剂制作的理论与实践均不成熟,本研究探讨中药汤剂肠安Ⅰ号方安慰剂的制作方法,为中药汤剂的双盲安慰剂对照临床试验提供技术支持。
方法：经过多次试验,最终采取以大米(炒至焦黄色)为辅料,配合5%原药煎制而成。
结果：(1)通过视觉模拟量表,对安慰剂的外观、口味及中药汤剂模拟效果进行评价。结果表明,肠安Ⅰ号方原药在外观、口味、中药汤剂模拟效果方面的得分分别为9.10±0.60、9.00±0.60、9.30±0.70。安慰剂的得分分别为8.20±1.30、7.40±0.90、9.10±0.70；两者比较,在外观方面无统计学差异(p>0.05)；在口味方面,两者比较,有统计学差异(p<0.05)。但在中药汤剂模拟效果评测的判定中,两者无统计学差异,均符合常人对中药的认知。(2)实验研究表明,肠安Ⅰ号方安慰剂对实验大鼠的内脏高敏感性、胃肠动力没有作用,没有镇痛及抗炎的作用。
结论：肠安Ⅰ号方安慰剂符合常人对中药汤剂的认知,外观与肠安Ⅰ号方相似,且无明显药理作用,可以作为安慰剂使用。
2肠安Ⅰ号方治疗IBS-D的临床疗效评价研究
目的：中药汤剂是中医药临床治疗IBS-D的主要剂型,目前尚未有使用中药汤剂治疗IBS-D的随机、双盲、安慰剂对照的临床试验报道。本研究采用规范的临床试验设计方法和公认的临床疗效评价指标,评价中药汤剂肠安Ⅰ号方治疗IBS-D的临床疗效及安全性。
方法：采用随机、双盲、安慰剂对照临床试验设计,对符合纳入标准,不符合排除标准IBS-D患者,由药品管理员按照入组顺序,根据随机信封的药物编码,制作并发放相应的研究药物。试验组予以肠安Ⅰ号方,150ml/袋,3/日；对照组予以安慰剂,150ml/袋,3/日,疗程均为8周。
结果：共纳入患者60例,试验组与对照组各30例,纳入全分析集(FAS)分析58例；纳入符合方案集(PP)分析56例。主要疗效评价指标包括IBS症状严重程度量表(IBS-SSS)的积分变化、明显缓解(AR)应答(Responder)的差异；次要疗效指标包括IBS-SSS的等级改善、IBS生活质量量表(IBS-QOL)的总积分及各个维度积分变化、医院焦虑与抑郁量表(HAD)焦虑子量表与抑郁子量表的积分变化、中医相关症状总积分及中医证型相关症状积分变化、排便相关症状改善；安全性指标包括不良事件及相关实验室检查。
(1)主要疗效指标：
1) IBS-SSS量表积分改善。FAS：试验组在基线期、用药后第2周、第4周、第6周、第8周的积分分别为242.52±69.84、213.56±93.4、198.83±92.45、169.04±92.31、125.30±78.94；对照组为265.39±97.92、214.63±84.37、212.29±91.93、209.73±107.54、194.01±96.53,经比较,两组间差异有统计学意义(P<0.05)。PP：试验组在基线期、用药后第2周、第4周、第6周、第8周的积分分别为242.52±69.84、213.56±93.4、198.83±92.45、169.04±92.31、125.30±78.94；对照组为260.28±99.45、210.36±83.8、210.81±87.82、204.43±104.82、188.05±91.34,经比较,两组间的差异有统计学意义(p<0.05)。FAS与PP的结论一致,试验组的疗效优于对照组。
2)AR应答。FAS：试验组有应答者25(89.3%)人,无应答者3(10.7%)人；对照组有应答者11(36.7%)人,无应答者19(63.3%)人；经比较,两组间差异有统计学意义(p<0.05)。PP：试验组有应答者25(89.3%)人,无应答者3(10.7%)人；对照组有应答者11(39.3%)人,无应答者17(60.7%)人；经比较,两组间差异有统计学意义p<0.05)。FAS与PP结论一致,试验组疗效优于对照组。
(2)次要疗效指标
1) IBS-SSS等级改善。试验组痊愈者9例,显效者1例,有效者7例,无效者11例；对照组痊愈者3例,显效者2例,有效者11例,无效者14例,经Ridit检验,两组间差异无统计学意义(p>0.05)。
2) IBS-QOL改善。IBS-QOL总积分：试验组在基线、用药后第4周、第8周积分分别为31.75±21.19、28.52±20.42、23.82±21.52；对照组分别为38.75±24.90、28.11±19.46、29.14±22.61。心境恶劣维度积分：试验组分别为35.83±27.05、30.69±24.62、23.33±26.03；对照组分别为45.21±27.75、31.15±20.72、34.06±27.70。行为障碍维度积分：试验组分别为37.76±25.13、32.78±23.75、29.72±25.64；对照组分别为42.62±31.15、32.26±24.25、33.33±25.38。自体意象维度积分：试验组分别为16.07±20.58、17.41±22.59、16.29±19.49；对照组分别为25.42±27.12、18.13±21.23、21.25±23.65。健康担忧维度积分：试验组分别为47.02±30.36、36.90±27.82、29.46±29.44；对照组分别为51.11±25.78、34.72±22.00、30.00±21.06。进食逃避维度积分：试验组分别为44.35±29.14、44.94±28.63、38.10±29.35；对照组分别为47.22±33.36、40.56±25.96、43.06±27.78。社会功能维度积分：试验组分别为22.99±20.42、20.83±18.91、18.08±21.87；对照组分别为28.75±25.09、19.58±18.18、22.08±21.19。性行为维度积分：试验组分别为18.75±19.98、18.75±20.27、13.84±22.91；对照组分别为33.75±37.16、18.33±27.41、17.92±25.99。关系拓展维度积分：试验组分别为20.24±21.57、18.45±19.43、15.77±18.33；对照组分别为26.11±26.87、19.72±22.15、18.89±23.05。经比较,IBS-QOL总积分及各个维度积分在两组间均无统计学差异(p>0.05)。
3)HAD积分。焦虑子量表积分：试验组在基线、用药后第4周、第8周积分分别为8.07±4.01、7.68±3.99、7.07±4.09；对照组分别为8.03±4.06、7.63±3.21、6.87±3.88；经比较,两组间差异无统计学意义(p>0.05)。抑郁子量表积分：试验组在基线、用药后第4周、第8周积分分别为7.96±2.92、8.04±3.02、7.96±3.31；对照组分别为8.37±3.65、7.80±3.08、7.27±3.52；经比较,两组间差异无统计学意义(p>0.05)。
4)中医症状积分。试验组在基线、用药后第4周、第8周中医症状总积分分别为24.75±7.53、20.75±8.93、16.82±8.12；对照组分别为22.67±9.02、19.07±9.80、19.17±9.66；经比较,两组间差异无统计学意义(p>0.05)。但试验组对中医症状总积分及肝脾不和型、脾胃虚弱型、脾肾阳虚型相关症状的改善趋势比对照组更为明显。
5)排便相关症状。试验组在腹痛指数、排便指数、性状指数、便急指数、感觉指数和粘液指数方面与对照组相比,差异均无统计学意义(p>0.05)。试验组在腹痛指数、排便指数、性状指数、便急指数、感觉指数、粘液指数方面均呈明显下降趋势；对照组在腹痛指数、性状指数、便急指数、粘液指数也呈下降趋势；但趋势不如试验组明显。
(3)安全性检查
研究中未发现明确与临床试验药物相关的、有临床意义的不良事件和实验室检查异常。
结论：肠安Ⅰ号方治疗IBS-D临床能够明显降低IBS-SSS积分,提高AR应答率,疗效优于安慰剂,临床未发现明确不良反应。表明肠安Ⅰ号方治疗IBS-D是临床有效安全的。次要疗效指标未能显示出统计学差异,考虑与指标本身的反应度低及临床研究的样本量不足相关,宜扩大样本量进一步研究。
3中医药治疗IBS的临床疗效评价指标比较研究
目的：我国IBS中医药临床疗效评价多采取复合指标评价的方式,与国外通行的疗效评价方式有一定的差距,罗马Ⅲ标准对IBS的临床疗效评价指标提出了推荐意见,但由于缺乏实际的数据支持而面临一定的争议。本研究以临床试验为依托,考察IBS临床研究中常用疗效评价指标的反应度,为IBS相关中医药临床试验的临床疗效评价指标的使用提供参考。
方法：以“排便相关症状”为有意义的临床变化,分别考察IBS-SSS、AR、IBS-QOL、HAD与排便相关症状的关系及其临床反应度。
结果：(1)IBS-SSS与排便相关症状、焦虑状态存在线性相关关系,其效应尺度为1.59,临床反应度较高。(2)AR的单次应答与排便相关症状存在线性相关关系。(3) IBS-QOL与排便相关症状线性相关关系不明显,与焦虑状态有一定的关联,效应尺度为0.61,具有中等反应度。(4)HAD中焦虑子量表、抑郁子量表积分与排状相关症状不存在线性相关关系,焦虑子量表的效应尺度为0.34,抑郁子量表的效应尺度为0.03,临床反应度较低。
结论：IBS-SSS临床反应度较好,与排便相关症状及焦虑状态明确相关,适合在临床疗效评价中使用；AR的单次应答与症状相关,由于在临床疗效评价过程中,常将多次应答组合成复合评价指标,因此需注意其“有临床意义”的界定；IBS-QOL与焦虑状态相关,与症状关系不明确,具有中等临床反应度,适合观察周期较长的临床研究使用；HAD临床反应度较低,不适合作为临床疗效评价指标使用。
There are three parts in this research, including manufacturing of placebo of Chang'anyihao Decoction, the clinical research of Chang' anyihao Decoction in treat-ing irritable bowel syndrome with diarrhea (IBS-D) and research of responsibility of common irritable bowel syndrome (IBS) clinical effect assessment indices.
1 Manufacturing of placebo of Chang'anyihao Decoction
Objective The lack of related theory and practical use of placebo in TCM decoction prevented higher quality of responding clinical trials. We exploited the manufacturing methods of placebo of Chang'anyihao Decoction to provide support for a dou-ble-blind, placebo-controlled trial of TCM decoction.
Methods We finally took stir-frying rice as the main excipients, and accompanied by 5% of Chang' anyihao Decoction to manufacture the placebo after several pilot trials.
Results (1) Visual analogue scales (VAS) was adopt to evaluate the appearance, taste and similarity to common TCM decoction. The score of appearance, taste and similar-ity to TCM decoction was 9.10±0.60、9.00±0.60、9.30±0.70 in Chang'anyihao De-coction, and of which in placebo was 8.20±1.30、7.40±0.90、9.10±0.70. Although there were significant differences in taste between two groups (p<0.05), there were no statistically significant differences between two drugs in appearance and similarity to TCM decoction (p>0.05). (2)Experiments also proved that the placebo exerted no ef-fect in visceral hypersensitivity, gastrointestinal motility and inflammation condition.
Conclusions Placebo of Chang'anyihao Decoction accorded with common sense and recognition of TCM decoction of ordinary people, and it can be taken as placebo for its similar appearance and pharmacological ineffective.
2 Clinical research of Chang'anyihao Decoction in treating IBS-D
Objective Decoction was the main preparation in the treatment of IBS-D in TCM practice, while there were no substantial evidences to prove the effectiveness of TCM decoction. We performed a clinical trial to evaluate the effectiveness and safety of Chang'anyihao Decoction.
Methods A randomized, double-blinded, placebo-controlled clinical trial design was adopted in the trial. Patients were given responding drugs by the drug administrator according to their inclusion sequences. The experiment group was given Chang'anyihao Decoction150ml three times a day, and the control group was given placebo 150ml three times a day. The treatment courses of both groups were 8 weeks.
Results Among 60 included patients,58 were screened for full analysis set (FAS), and 56 were screened per-protocol set (PPS). The results were as follows:
(1) Primary outcomes
1) Improvement of irritable bowel syndrome symptom severity score (IBS-SSS). In FAS, the score were 242.52±69.84、213.56±93.4、198.83±92.45、169.04±92.31、125.30±78.94 in baseline,2 weeks after treatment,4 weeks after treatment,6 weeks after treatment and 8 weeks after treatment in experiment group, and in control group, the score were 265.39±97.92、214.63±84.37、212.29±91.93、209.73±107.54、194.01±96.53 respectively. In PP, the score were 242.52±69.84、213.56±93.4、198.83±92.45、169.04±92.31、125.30±78.94 from baseline to 8 weeks after treatment in experiment group, and in control group, the score were 260.28±99.45、210.36±83.8、210.81±87.82、204.43±104.82、188.05±91.34 respectively. The differences were statistically significant between the two groups (p<0.05), FAS and PP had the same results.
2) Comparison of adequate relief (AR). In FAS, the responder rate was 89.3%(25/28) in experiment group and the rate is 36.7%(11/30) in control group. In PP, the re-sponder rate was 89.3%(25/28) and 39.3%(11/28) respectively. The differences were statistically significant between the two groups (p<0.05), FAS and PP had the same results.
(2) Secondary outcomes
Secondary outcomes included the ranked improvement of IBS-SSS, change in irrita-ble bowel syndrome- quality of life questionnaire (IBS-QOL) total score and subscale score, score change in hospital anxiety and depression scale (HAD), TCM symptoms and defecation related symptoms. To all secondary outcomes, there were no statisti-cally significant differences between the two groups (p>0.05). But to TCM symptoms and its subtype symptoms, and the symptoms indices of defecation related symptoms, the experiment group manifested a better tendency in improvement.
(3) Assessment of safety
There were no specific adverse events and laboratory test concerned to research drugs happened.
Conclusions Chang'anyihao was effective and safe in clinical practice with a definite improvement in IBS-SSS score, a higher AR responder rate, and less adverse reaction.
3 Research of responsibility of common IBS clinical effect assessment indices
Objective Rome III proposed suggestions of clinical effect assessment indices for IBS clinical trials according to literature, while the suggestions lacked valid data support and in China, researches of these suggested indices were even less. We conducted the research to evaluate the responsibility of each common index for further IBS clinical trial use.
Methods Indices of IBS-SSS, AR, IBS-QOL, HAD were appraised taken defecation related symptoms as clinical meaningful references.
Results (1) The score of IBS-SSS had a linear regression with defecation related symptoms and anxiety score, the responsibility was high with an effect size of 1.59. (2) Response to each AR response was related to defecation related symptoms. (3) The score of IBS-QOL did not correlate with defecation related symptoms, but had a rela-tionship with anxiety with an effect size of 0.61. (4) Anxiety and depression score measured by HAD had no relationship with defecation related symptoms and the ef-fect size was low.
Conclusions IBS-SSS was a good tool for IBS clinical trials for its high responsibility and relation with defecation related symptoms. AR singly assessment reflected the clinical symptoms change, for it always been changed for a kind of complex assess-ment indices, attention should be paid to the clinical meaning. IBS-QOL may be used for long term research for it was insensitive to short term clinical changes. HAD was improper for IBS clinical effect evaluation.
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