【摘要】：[研究背景]消化系統(tǒng)腫瘤術(shù)后胃癱綜合征(Postsurgicalgastroparesis Syndrome, PGS)指消化系統(tǒng)腫瘤手術(shù)后以胃流出道非機(jī)械性梗阻為主要特征的一種功能性疾病,也是一種胃動(dòng)力缺乏性疾病。其發(fā)病率有上升趨勢(shì),胃癱發(fā)病率國內(nèi)報(bào)道為0.6%-7%,國外報(bào)道為5%-10%。消化系統(tǒng)腫瘤在中國的發(fā)病率逐年升高,同時(shí)醫(yī)學(xué)技術(shù)的進(jìn)步也使得早期消化系統(tǒng)腫瘤患者手術(shù)后獲得了較長的生存期,不適的癥狀和漫長的術(shù)后并發(fā)癥降低了患者的生活質(zhì)量,對(duì)患者術(shù)后生活信心的恢復(fù)造成不良影響。現(xiàn)代醫(yī)學(xué)治療PGS的療效有限。傳統(tǒng)中醫(yī)藥治療PGS的國內(nèi)報(bào)道較多,不管采用中藥內(nèi)治法還是外治法,其治療有效率普遍在80%以上,中醫(yī)與西醫(yī)治療該病有效率差異明顯。通過檢索CNKI文獻(xiàn)庫與Pubmed文獻(xiàn)庫發(fā)現(xiàn),盡管中藥治療PGS的中文報(bào)道較多,其缺點(diǎn)是諸多的研究結(jié)論缺乏高級(jí)別循證醫(yī)學(xué)證據(jù)支持,僅為病例回顧分析研究或簡(jiǎn)單的病例對(duì)照研究；而Pubmed上目前仍檢索到外用中藥治療PGS的任何研究報(bào)道。因此,設(shè)計(jì)一個(gè)具有較高級(jí)別循證醫(yī)學(xué)證據(jù)的臨床試驗(yàn)來證實(shí)中藥治療PGS的臨床療效,將有助于改善PGS的治療現(xiàn)狀,更好的發(fā)揮中醫(yī)藥的優(yōu)勢(shì)。課題組前期對(duì)消化系統(tǒng)腫瘤術(shù)后胃癱患者的中醫(yī)證型規(guī)律進(jìn)行研究,局部辨證以“寒證”為主,以“溫陽散寒、行氣化瘀”為治法自擬“胃癱外敷方”,采用前瞻性、多中心、隨機(jī)雙盲、安慰劑平行對(duì)照的RCT臨床課題設(shè)計(jì)治療消化系統(tǒng)腫瘤術(shù)后PGS,以期為中醫(yī)中藥治療腫瘤術(shù)后PGS增加高級(jí)別的循證醫(yī)學(xué)證據(jù),繼而使國內(nèi)外更多的患者受益。[研究目的]1.探討“胃癱外敷方”治療消化系統(tǒng)腫瘤術(shù)后PGS的臨床療效；2.評(píng)價(jià)“胃癱外敷方”治療消化系統(tǒng)腫瘤術(shù)后PGS安全性。[研究方法]本課題應(yīng)用前瞻性、多中心、隨機(jī)雙盲、安慰劑平行對(duì)照的臨床研究設(shè)計(jì),并且整個(gè)研究過程接受課題管理部門北京市科委所安排的北京岐黃藥品臨床研究中心進(jìn)行第三方實(shí)時(shí)監(jiān)察。在多次方案論證會(huì)后確定最終研究方案,完成患者招募前的準(zhǔn)備工作,同時(shí)通過四個(gè)研究中心的倫理審查,進(jìn)行國際臨床試驗(yàn)注冊(cè),培訓(xùn)四個(gè)分中心的研究者,統(tǒng)一安排藥物購入,制劑室根據(jù)循證醫(yī)學(xué)中心提前審定的盲底籌備制作藥品(包括試驗(yàn)藥和安慰劑藥)。隨后根據(jù)入組標(biāo)準(zhǔn)招募腫瘤術(shù)后PGS患者,完成入組前篩選,包括胃腸鏡、消化道造影、胸腹部CT或腹部立位片、血常規(guī)、肝腎功能、尿常規(guī)、便常規(guī)+潛血檢查、心電圖等檢查。根據(jù)患者入組次序分發(fā)每個(gè)中心已經(jīng)完成設(shè)盲的藥物,記錄患者治療第1、3、5、7、14天的胃動(dòng)力恢復(fù)時(shí)間、胃癱癥狀評(píng)分、胃引流及嘔吐量,記錄不良反應(yīng)�；颊咧委熗瓿珊筮M(jìn)行出組檢查(與入組時(shí)檢查項(xiàng)目相同)后出組,同時(shí)按照患者愿望無償領(lǐng)取2周的“胃癱外敷方”真藥繼續(xù)治療。所有病例數(shù)據(jù)錄入后由北京中醫(yī)藥大學(xué)循證醫(yī)學(xué)中心鎖定數(shù)據(jù),在課題負(fù)責(zé)人和循證醫(yī)學(xué)中心、第三方岐黃研究中心監(jiān)察人員三方在場(chǎng)下揭盲,完成數(shù)據(jù)統(tǒng)計(jì)分析。最后明確“胃癱外敷方”治療腫瘤術(shù)后PGS的臨床療效,并進(jìn)行安全性評(píng)價(jià)。[研究結(jié)果]1.課題從啟動(dòng)、實(shí)施、完成到最后揭盲,均在嚴(yán)格的質(zhì)量控制下完成,符合課題預(yù)期的質(zhì)量控制標(biāo)準(zhǔn)。整個(gè)課題所開展并全部完成的質(zhì)控項(xiàng)目有：倫理申報(bào)、上會(huì)討論及審批、循證醫(yī)學(xué)中心根據(jù)盲法要求設(shè)盲、藥物統(tǒng)一購買、全程質(zhì)量控制、制劑室根據(jù)研究項(xiàng)目書編寫藥品制備流程、在國際網(wǎng)站上進(jìn)行臨床試驗(yàn)登記注冊(cè)、對(duì)內(nèi)四個(gè)中心所有研究者進(jìn)行培訓(xùn)、對(duì)外多渠道進(jìn)行患者招募、第三方監(jiān)察單位進(jìn)行每月質(zhì)量監(jiān)察并出具報(bào)告、病例數(shù)達(dá)標(biāo)后進(jìn)行循證醫(yī)學(xué)數(shù)據(jù)管理、兩次標(biāo)準(zhǔn)化揭盲。細(xì)致規(guī)范的質(zhì)控過程保證了該課題數(shù)據(jù)的客觀性和準(zhǔn)確性。2.本課題按要求招募120例腫瘤術(shù)后PGS患者入組,歷時(shí)24個(gè)月,其中2例因不良反應(yīng)事件提前終止試驗(yàn),1例違背試驗(yàn)方案退出試驗(yàn),12例受試者自動(dòng)退出,共計(jì)105例患者完成本次研究,療程為14天�；�分析示試驗(yàn)藥組和安慰劑組在患者年齡、藥物過敏史、術(shù)后留置鼻胃管、中藥治療史、術(shù)后胃癱分級(jí)、胃癱癥狀分級(jí)、腫瘤類型、腫瘤轉(zhuǎn)移部位、手術(shù)名稱、手術(shù)切口類型方面,P0.05,無統(tǒng)計(jì)學(xué)差異,兩組在人口學(xué)特征方面具有可比性。入組檢查包括兩組病人在血常規(guī)、尿常規(guī)、便常規(guī)+潛血、肝功能、腎功能、離子水平和心電圖等方面,療效基線分析方面包括入組時(shí)是否留置鼻胃管與入組胃癱癥狀評(píng)分,以上兩組間無明顯差異(P0.05)。因此,兩組PGS患者在入組基線上具有可比性,符合隨機(jī)設(shè)計(jì)。3.根據(jù)課題設(shè)定的臨床有效標(biāo)準(zhǔn),FAS集中60例試驗(yàn)組患者中41例為臨床有效,有效率為68.33%；60例安慰劑組患者中25例臨床有效,有效率為41.67%,FAS集中兩組病人在有效率上有統(tǒng)計(jì)學(xué)差異,試驗(yàn)藥組有效率高于安慰劑組(P=0.003)。PPS集為全部與試驗(yàn)方案相符、依從性好、試驗(yàn)期內(nèi)未服禁止藥、順利完成研究方案規(guī)定的隨訪過程、同時(shí)完成CRF表規(guī)定填寫內(nèi)容的病例,試驗(yàn)藥組為45例,安慰機(jī)組為43例,其中試驗(yàn)藥組有效35例,無效10例,有效率為77.78%；安慰機(jī)組有效19例,無效24例,有效率為44.19%,PPS集中兩組病人在有效率上有統(tǒng)計(jì)學(xué)差異,試驗(yàn)藥組有效率高于安慰劑組(P=0.001)。扣除中心效應(yīng)后分析發(fā)現(xiàn)“胃癱外敷方”治療PGS的臨床療效與安慰劑相比有統(tǒng)計(jì)學(xué)差異(P=0.002)。4.次要結(jié)局指標(biāo)包括兩組治療有效時(shí)間、鼻胃管引流量變化、胃癱主要癥狀前后變化程度、胃癱癥狀評(píng)分變化,研究發(fā)現(xiàn)①治療有效時(shí)間使用生存分析比較兩組差異。FAS集(P=0.017)和PPS集(P=0.006)中兩組病人在治療有效所需時(shí)間上均有統(tǒng)計(jì)學(xué)差異,試驗(yàn)藥組治療有效所需時(shí)間小于安慰劑組。②鼻胃管引流量變化在治療第1天、第3天、第5天、第7天、第14天的組間差異,FAS集和PPS集中兩組病人在胃管引流量上無統(tǒng)計(jì)學(xué)差異。③胃癱主要癥狀前后變化程度方面,FAS集和PPS集中兩組病人在胃癱主要癥狀(不能正常量的進(jìn)餐、餐后極度飽脹感)前后變化上有統(tǒng)計(jì)學(xué)差異,其余癥狀無統(tǒng)計(jì)學(xué)差異。④胃癱癥狀評(píng)分變化方面,FAS集和PPS集中不同時(shí)間的胃癱癥狀評(píng)分有統(tǒng)計(jì)學(xué)差異,兩組病人在胃癱癥狀評(píng)分上無統(tǒng)計(jì)學(xué)差異。5.試驗(yàn)藥組發(fā)現(xiàn)3例不良反應(yīng)患者,不良反應(yīng)在53例試驗(yàn)藥患者(不含脫落的7例)中發(fā)生率為5.66%；安慰劑組未發(fā)現(xiàn)不良反應(yīng)中止治療的患者。試驗(yàn)藥組皮膚不良反應(yīng)發(fā)生率,與安慰劑組比較無統(tǒng)計(jì)學(xué)差異(P=0.244)。患者經(jīng)過治療后的血尿便常規(guī)、肝腎功能、電解質(zhì)水平和心電圖等檢查出現(xiàn)異常值的發(fā)生率在兩組中無明顯差別(P0.05)。[研究結(jié)論]1.在試驗(yàn)研究前充分論證的基礎(chǔ)上,完成本次前瞻性、多中心、隨機(jī)雙盲、安慰劑平行對(duì)照的臨床試驗(yàn),課題設(shè)計(jì)嚴(yán)密、實(shí)施過程嚴(yán)謹(jǐn),第三方監(jiān)管嚴(yán)格,為循證醫(yī)學(xué)提供高級(jí)別證據(jù),結(jié)論真實(shí)可靠。2.主要結(jié)局指標(biāo)分析發(fā)現(xiàn),寒熱理論指導(dǎo)下的中藥外敷能夠提高消化系統(tǒng)腫瘤術(shù)后PGS患者的臨床有效率,胃癱外敷方與安慰劑治療PGS的臨床有效率有顯著差別,胃癱外敷方療效確切。3.次要結(jié)局指標(biāo)分析發(fā)現(xiàn),胃癱外敷方治療有效所需時(shí)間小于安慰劑,且具有統(tǒng)計(jì)學(xué)差異；在治療第1天、第3天、第5天、第7天、第14天的鼻胃管引流量變化方面,兩組無統(tǒng)計(jì)學(xué)差異；兩組在胃癱主要癥狀(不能正常量的進(jìn)餐、餐后極度飽脹感)改善方面有統(tǒng)計(jì)學(xué)差異,胃癱外敷方優(yōu)于安慰劑,而在“惡心、干嘔、嘔吐、胃部脹滿、沒有食欲、腹部脹大、胃或腹部明顯增大”這7個(gè)癥狀方面,兩組無統(tǒng)計(jì)學(xué)差異。兩組在不同時(shí)間的胃癱癥狀評(píng)分有統(tǒng)計(jì)學(xué)差異,但兩組病人在胃癱癥狀評(píng)分上無統(tǒng)計(jì)學(xué)差異。因此,在治療后的鼻胃管引流量變化方面、治療后“惡心、干嘔、嘔吐、胃部脹滿、沒有食欲、腹部脹大、胃或腹部明顯增大”7個(gè)癥狀控制方面以及治療后的胃癱癥狀評(píng)分改善方面,不能認(rèn)為胃癱外敷方優(yōu)于安慰劑。4.中藥外敷治療方式可以引起皮膚的過敏反應(yīng),使用“胃癱外敷方”治療PGS患者時(shí)皮膚過敏反應(yīng)(1例中度干性脫皮水皰瘙癢,1例輕度皮膚瘙癢)發(fā)生率為5.66%,與安慰劑組比較未發(fā)現(xiàn)顯著性差異(P=0.244)。與安慰劑相比,未發(fā)現(xiàn)“胃癱外敷方”治療PGS患者時(shí)增加患者血常規(guī)、生化檢查(肝功能、腎功能、離子)、尿常規(guī)、便常規(guī)+潛血、心電圖、胃鏡、腸鏡、消化道造影、腹部立位片、CT檢查等指標(biāo)的惡化風(fēng)險(xiǎn)。5.本研究證實(shí)“胃癱外敷方”治療消化系統(tǒng)腫瘤術(shù)后PGS的臨床有效率高于安慰劑,治療有效所需時(shí)間小于安慰劑,“胃癱外敷方”可以讓消化系統(tǒng)腫瘤術(shù)后屬“寒證”的PGS病人獲益。
[Abstract]:[background] Postsurgicalgastroparesis Syndrome (PGS) after digestive system tumor operation refers to a functional disorder characterized by the non mechanical obstruction of the gastric flow after the operation of the digestive system, and also a kind of gastric motility deficiency. The incidence of the disease has a rising trend, and the incidence of gastroparesis is reported to be 0.6%-7% at home. It is reported that the incidence of 5%-10%. digestive system tumor in China is increasing year by year, and the progress of medical technology has also made the early digestive system tumor patients get a longer survival period. The symptoms of discomfort and the long postoperative complications reduce the quality of life of the patients and the recovery of life confidence after the operation of the patients. The effect of modern medical treatment of PGS is limited. There are many domestic reports on traditional Chinese medicine for the treatment of PGS. The effective rate of the treatment is more than 80%, and the effective rate of the treatment of the disease is more than 80%. The Chinese medicine and the western medicine treatment of the disease have obvious difference. The Chinese Medicine Library and the Pubmed literature database have been found, although the Chinese medicine is used to treat PGS in Chinese There are many reports, its shortcomings are that many research conclusions lack the support of high level evidence-based medicine, only a retrospective case study or a simple case control study, and Pubmed is still retrieving any research report on the treatment of PGS by external use of traditional Chinese medicine. Therefore, a clinical trial with a higher level of evidence-based medical evidence is designed. The clinical effect of traditional Chinese medicine in the treatment of PGS will help to improve the status of the treatment of PGS and give full play to the advantages of traditional Chinese medicine. A prospective, multicenter, randomized, double blind, placebo-controlled, parallel controlled RCT clinical project was designed for the treatment of PGS after the operation of digestive system tumor, in order to increase the level of evidence-based medical evidence for PGS after the treatment of tumor surgery in traditional Chinese medicine, and then benefit more patients at home and abroad. [Objective]1. to explore the treatment of digestive system with the external compress of gastroparesis The clinical effect of PGS after tumor operation; 2. evaluate the PGS safety after the treatment of digestive system tumor after the treatment of digestive system tumor. [research method] this subject applies prospective, multicenter, double-blind, placebo parallel control clinical research design, and the whole research process accepts the Beijing Qi Huang arranged by the Beijing municipal science and Technology Commission of the subject management department. The center for drug clinical research conducted the third party real-time monitoring. After several plans, the final research plan was determined, the preparatory work was completed before the recruitment of the patients. At the same time, the international clinical trial registration was carried out through the ethical review of the four research centers, the four sub centers were trained, the drug purchase was arranged in a unified way, and the preparation room was based on evidence-based evidence. Drugs (including test drugs and placebo drugs) were prepared by the medical center in advance. Then PGS patients after tumor surgery were recruited according to the criteria of entry group, and pre group screening was completed, including gastrointestinal endoscopy, digestive tract angiography, thoracic and abdominal CT or abdominal orthostatic tablets, blood routine, liver and kidney function, urine routine, routine + Occult examination, electrocardiogram examination. According to the order of the patients, each center had been dispensed with a blind drug, the recovery time of gastric motility, the score of gastroparesis, gastric drainage and vomiting were recorded, and the adverse reactions were recorded. After the treatment was completed, the group was examined (the same as that in the group), and the patient's desire was unpaid in accordance with the patient's desire. After 2 weeks of "gastroparesis external compress" to continue the treatment, all case data were recorded by the evidence based medicine center of Beijing University of Chinese Medicine, in the subject and evidence-based medical center, the third Fang Qi Huang Research Center, three party inspectors under the presence of blindness, completed the statistics and analysis. Finally, the "gastroparesis external compress" treatment. The clinical efficacy of PGS after the treatment of tumor and the evaluation of safety. [results]1. subjects from starting, implementing, completing to final blindness are all completed under strict quality control, conforming to the expected quality control standards of the subject. The whole project carried out and completed the quality control items: ethical declaration, discussion and approval, evidence-based medicine The center should be blind according to the requirements of the blind law, the drug purchase, the whole quality control, the preparation process of the drug preparation room based on the research project, the registration of clinical trials on the international website, the training of all the four centers in the inner center, the recruitment of patients in the foreign channels, and the monthly quality supervision of the third party supervision units. The data management of evidence-based medicine and two standardized blindness were carried out after the number of cases reached the standard. The objective and accuracy of the detailed standard quality control process ensured the objective and accuracy of the data..2. this subject was recruited in 120 cases after the operation of the tumor for 24 months, of which 2 cases were terminated in advance because of adverse events and 1 cases were violated. The back test scheme withdrew from the test. 12 subjects were automatically withdrawn. A total of 105 patients completed the study for 14 days. The baseline analysis showed the age of the drug group and the placebo group in the patient's age, the history of drug allergy, the retention of the nasogastric tube after operation, the history of Chinese medicine treatment, the classification of gastroparesis, the classification of gastroparesis symptoms, the type of tumor, the site of tumor metastasis, and the name of the operation. There were no statistical differences between the two groups. The two groups were comparable in demographic characteristics. The group examination included two groups of patients in the blood routine, urine routine, routine + occult blood, liver function, renal function, ion level and electrocardiogram, including whether the nasogastric tube was indwelling with the group of gastroparesis when the group was entered. There was no significant difference in symptom score between the two groups (P0.05). Therefore, two groups of PGS patients were comparable in the baseline of the entry, which accorded with the randomized design of.3. according to the clinical effective criteria set according to the subject. 41 of the 60 patients in the FAS concentration test group were clinically effective and effective at 68.33%; 25 of the 60 placebo group were clinically effective and had an effective rate of 4. 1.67%, FAS concentration of two groups of patients in the effective rate of statistical difference, the effectiveness of the test group is higher than the placebo group (P=0.003).PPS set is all consistent with the test plan, compliance is good, in the test period did not take the prohibition drug, the smooth completion of the follow-up process prescribed by the research program, the same time the CRF table completed the contents of the cases, the test drug group is 45 For example, the consolation unit was 43 cases, of which 35 cases were effective in the experimental group, 10 cases were invalid, the effective rate was 77.78%, the consolation unit was 19 cases, 24 cases were invalid, the effective rate was 44.19%, the effective rate of the PPS concentration two groups was statistically different, the effective rate of the experimental group was higher than that of the placebo group (P=0.001). After deducting the central effect, the analysis found "the external application side of gastroparesis". The therapeutic effect of PGS was statistically different from placebo (P=0.002).4. secondary outcome indicators including two groups of effective time, changes in nasal gastric tube flow, changes in the main symptoms of gastroparesis, and the change of gastroparesis symptom score. The study found that two groups of difference.FAS set (P=0.017) were compared with the analysis of effective time use survival analysis (P=0.017). In the PPS set (P=0.006), two groups of patients were statistically different in the time required for effective treatment. The time required for effective treatment in the experimental group was less than that in the placebo group. (2) the variation in the flow of nasal gastric tube at first days, third days, fifth days, seventh days and fourteenth days, and there was no statistical difference between the FAS set and the PPS concentration group in the gastric tube flow rate. (3) the change degree of the main symptoms of gastroparesis before and after the main symptoms of FAS and PPS, there were statistical differences between the two groups of the main symptoms of gastroparesis (not the normal meal, the postprandial satiety feeling), and the other symptoms were not statistically different. (4) the score of gastroparesis symptom score, FAS set and PPS concentration in different time scores of gastroparesis symptom score Statistical differences, there was no statistical difference between the two groups in the score of gastroparesis, and 3 cases of adverse reactions were found in the.5. test group, and the incidence of adverse reactions was 5.66% in 53 cases (7 without shedding); the placebo group did not find the patients with ADR treatment. The incidence of ADR in the experimental group and the consolation of the placebo group. There was no statistical difference between the two groups (P=0.244). There was no significant difference in the incidence of abnormal values in the two groups (P0.05). [conclusion]1., based on sufficient demonstration before the test, completed this prospective, multicenter, randomized, double blindness. The clinical trials of consolation parallel control were strictly designed, the implementation process was rigorous, the third party supervision was strict, and the evidence based on the evidence-based medicine was provided. The conclusion of the true and reliable.2. main outcome indicators found that the external application of Chinese medicine under the guidance of the cold and heat theory could improve the clinical efficiency of the PGS patients after the digestive system tumor operation, and the external application of gastroparesis. The clinical efficiency of PGS with placebo was significantly different. The effective.3. secondary outcome index analysis showed that the time required for the treatment of gastroparesis external application was less than that of placebo, and the difference was statistically significant. There was no statistical difference between the two groups in the first days, the fifth days, the seventh days, and fourteenth days of the nasal gastric tube flow. Differences in the two groups were statistically different in the main symptoms of gastroparesis (not normal food intake, postprandial satiety feeling). The external application of gastroparesis was superior to placebo, while in "nausea, vomiting, vomiting, stomach distention, no appetite, abdominal distention, stomach or abdominal enlargement", the two groups were not statistically different. The two groups were not. There was a statistical difference between the two groups at the same time, but there was no statistical difference in the score of the gastroparesis symptoms in the two groups. Therefore, after treatment, the changes in the flow rate of the nasal gastric tube after treatment were "nausea, vomiting, vomiting, stomach swell, no appetite, abdominal distention, gastric or abdominal enlargement" in 7 symptoms control and after treatment. As for the improvement of gastroparesis symptom score, it is not considered that the external application of gastroparesis is superior to the placebo.4. external application, which can cause the allergic reaction of the skin. The skin allergic reaction (1 cases of moderate dry blister pruritus, 1 cases of mild skin pruritus) in the treatment of PGS patients is 5.66%, compared with the placebo group. The significant difference (P=0.244) was found. Compared with placebo, the risk of worsening of blood routine, biochemical examination (liver function, renal function, ion), routine urine, routine + occult blood, electrocardiogram, gastroscope, enteroscopy, gastroenteroscopy, gastroenterography, abdominal erect, CT examination, and other indicators of worsening risk for PGS were not found in the treatment of patients with "gastroparesis external compress" in the treatment of patients. The clinical efficiency of PGS after the treatment of digestive system tumor is higher than that of placebo. The time required for the treatment is less than that of the placebo. "The external application of gastroparesis" can benefit the PGS patients who are "cold syndrome" after the digestive system tumor operation.
【學(xué)位授予單位】：北京中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R735
，

本文編號(hào)：2161369