本文關(guān)鍵詞： 安慰劑 臨床試驗(yàn) 乳腺癌術(shù)后上肢水腫 溫通消腫外敷方 中藥　出處：《北京中醫(yī)藥大學(xué)》2015年博士論文　論文類型：學(xué)位論文

【摘要】：[研究背景]乳腺癌術(shù)后上肢水腫(Breast cancer related lymphedema, BCRL)是乳腺癌病人手術(shù)后常見的并發(fā)癥之一,常伴許多不適癥狀,目前仍無法治愈,且具有終身發(fā)病的風(fēng)險(xiǎn),BCRL患者因此在身體、精神上承受巨大的痛苦而顯著降低了患者的生活質(zhì)量。隨著近年來乳腺癌發(fā)病率的增高、5年生存率的改善,BCRL已經(jīng)成為乳腺癌術(shù)后患者一個(gè)棘手的問題�，F(xiàn)代醫(yī)學(xué)治療BCRL的有效手段非常有限,目前多主張采用物理治療為主,最佳治療的有效率也不甚理想。傳統(tǒng)中醫(yī)藥治療BCRL的國內(nèi)報(bào)道較多,不管中藥內(nèi)治還是外治,其治療有效率普遍在80-100%,中西醫(yī)治療差異顯著。對比Pubmed和CNKI文獻(xiàn)庫后發(fā)現(xiàn),盡管中藥治療BCRL的中文報(bào)道較多,但缺點(diǎn)是這些研究結(jié)論缺乏高級別循證醫(yī)學(xué)證據(jù)支持,僅為病例回顧分析或簡單的病例對照研究；而Pubmed上目前仍沒有中藥治療BCRL的任何研究報(bào)道。因此,設(shè)計(jì)一個(gè)具有較高級別循證醫(yī)學(xué)證據(jù)的臨床試驗(yàn)來驗(yàn)證中藥治療BCRL的臨床療效,將有助于改善BCRL的治療現(xiàn)狀,更好的發(fā)揮中醫(yī)的優(yōu)勢。課題組前期對乳腺癌術(shù)后患者的中醫(yī)證型規(guī)律進(jìn)行研究,發(fā)現(xiàn)溫陽為主的治療是乳腺癌術(shù)后的主要治療大法,在此基礎(chǔ)上,以“溫陽益氣,利水消腫”為大法自擬“溫通消腫外敷方”,采用隨機(jī)、雙盲、安慰劑平行對照、多中心的臨床課題設(shè)計(jì)治療BCRL,以期待通過高級別臨床試驗(yàn)將中藥治療BCRL推向世界。[研究目的]1.探討“溫通消腫外敷方”治療BCRL的臨床療效；2.評價(jià)“溫通消腫外敷方”治療BCRL的安全性。[研究方法]本課題采用前瞻性的隨機(jī)、雙盲、安慰劑平行對照、多中心的臨床研究設(shè)計(jì),同時(shí)接受課題資助方北京市科委指派的北京岐黃藥品臨床研究中心全程監(jiān)察。在多次方案論證后確定最終研究方案,完成患者招募前的準(zhǔn)備工作,包括通過四個(gè)研究中心的倫理審查,完成國際臨床試驗(yàn)注冊,培訓(xùn)四個(gè)中心的研究者,協(xié)調(diào)藥品采購,制劑室依據(jù)循證醫(yī)學(xué)中心預(yù)先設(shè)定的盲底準(zhǔn)備藥品濃煎劑(試驗(yàn)藥和安慰劑藥)。隨后根據(jù)入組標(biāo)準(zhǔn)招募BCRL患者,完成入組檢查,包括上肢動(dòng)靜脈B超、腋窩淋巴結(jié)B超、血常規(guī)、尿常規(guī)、便常規(guī)、肝腎功能和電解質(zhì)檢查�；颊吒鶕�(jù)入組順序領(lǐng)取每個(gè)中心已經(jīng)預(yù)先設(shè)盲的藥物,記錄患者治療第0、3、5、7、14日的臂圍、并填寫上肢功能評價(jià)表(DASH),記錄不良反應(yīng)�；颊咧委熃Y(jié)束后完成出組檢查(與入組時(shí)檢查項(xiàng)目相同)后出組,并可根據(jù)意愿免費(fèi)領(lǐng)取14天“溫通消腫外敷方”真藥繼續(xù)治療。所有病例數(shù)據(jù)錄入后由循證醫(yī)學(xué)中心鎖定數(shù)據(jù),在循證醫(yī)學(xué)、岐黃監(jiān)察人員和課題負(fù)責(zé)人三方在場下揭盲,完成數(shù)據(jù)統(tǒng)計(jì)分析。最后明確“溫通消腫外敷方”治療BCRL的臨床療效,并進(jìn)行安全性評價(jià)。[研究結(jié)果]1.課題從啟動(dòng)、實(shí)施到最后揭盲,在嚴(yán)格的質(zhì)量控制下完成,基本符合課題預(yù)期的質(zhì)量控制標(biāo)準(zhǔn)。整個(gè)課題完成的質(zhì)控內(nèi)容包括：倫理審核、循證醫(yī)學(xué)中心編盲設(shè)盲、藥品統(tǒng)一采購和質(zhì)量把關(guān)、制劑室設(shè)計(jì)藥品制備流程、國際臨床試驗(yàn)注冊、研究者培訓(xùn)、患者招募、第三方每月質(zhì)量監(jiān)察、循證醫(yī)學(xué)數(shù)據(jù)管理、標(biāo)準(zhǔn)化揭盲。以上質(zhì)控的完成保證了課題數(shù)據(jù)的準(zhǔn)確性和真實(shí)性。2.本課題按要求招募96例BCRL患者入組,歷時(shí)18個(gè)月,其中4例患者因不良反應(yīng)中途退出研究,8例患者脫落失訪,共計(jì)84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、乳腺癌手術(shù)方式、腋窩淋巴結(jié)轉(zhuǎn)移情況、藥物過敏史、中西醫(yī)治療史、臨床分期、水腫分級等方面無明顯差(P0.05),入組時(shí)兩組的臂圍測定值和DASH評分值無明顯差別(P0.05),入組檢查提示兩組病人在血常規(guī)、尿常規(guī)、便常規(guī)、肝腎功能、電解質(zhì)水平和心電圖等方面無明顯差異(P0.05)�？傊�,兩組BCRL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),39例試驗(yàn)組患者中20例為臨床有效,有效率為51.3%；45例安慰劑組患者中31例臨床有效,有效率為68.9%,兩組有效率之間差異無顯著性(P=0.12)。分層分析示四個(gè)中心有效率分別為55.6%、50.0%、72.7%和27.3%,中心之間無顯著性差異(P0.05)�？鄢行男�(yīng)后,試驗(yàn)藥組和安慰劑組有效率仍無顯著差異。符合方案數(shù)據(jù)分析集分析后結(jié)論仍不變。4.次要結(jié)局指標(biāo)分析發(fā)現(xiàn),隨著治療時(shí)間的延長,觀察指標(biāo)(臂圍和上肢功能DASH評分)不斷改善,但臂圍變化不如DASH評分變化明顯。治療前后觀察指標(biāo)的變化在試驗(yàn)藥組和安慰劑組之間無明顯差異(Z=-0.94,P=0.35 and Z=-1.81,P=0.07);上肢功能改善的生存分析發(fā)現(xiàn)安慰劑組達(dá)到臨床有效標(biāo)準(zhǔn)約在第6.23天,試驗(yàn)藥組患者達(dá)到上肢功能DASH有效標(biāo)準(zhǔn)平均需要7.26天,兩組有效病人達(dá)到臨床有效時(shí)間之間無明顯差異(P=0.37)。5.試驗(yàn)藥組發(fā)現(xiàn)3例皮膚Ⅱ度過敏反應(yīng)患者,不良反應(yīng)發(fā)生率為7%,此外試驗(yàn)藥組發(fā)現(xiàn)1例感冒發(fā)燒患者；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,與安慰劑組比較未發(fā)現(xiàn)顯著性差異(P=0.11)。治療后發(fā)現(xiàn)的血常規(guī)、尿常規(guī)、便常規(guī)、肝腎功能、鉀鈉氯離子水平和心電圖等指標(biāo)異常情況在兩組中無明顯差別(P0.05)。[研究結(jié)論]1.在充分論證的基礎(chǔ)上,完成本次隨機(jī)、雙盲、安慰劑平行對照、多中心的臨床課題設(shè)計(jì),課題設(shè)計(jì)嚴(yán)謹(jǐn)、實(shí)施過程監(jiān)管嚴(yán)格,為循證醫(yī)學(xué)高級別證據(jù),結(jié)論真實(shí)。2.主要結(jié)局指標(biāo)分析發(fā)現(xiàn),寒熱理論指導(dǎo)下的溫?zé)嵬夥竽軌蛱岣呷橄侔┬g(shù)后上肢水腫的臨床有效率,而溫通消腫外敷方和安慰劑治療BCRL的臨床有效率無顯著差別,溫通消腫外敷方不具有治療優(yōu)勢。3.次要結(jié)局指標(biāo)分析發(fā)現(xiàn),溫通消腫外敷方和安慰劑均可改善患肢臂圍和上肢功能,但臂圍變化不如DASH評分變化明顯,兩種指標(biāo)的改善程度在試驗(yàn)藥組和安慰劑組之間無明顯差異。兩組病人上肢功能改善達(dá)有效標(biāo)準(zhǔn)所需時(shí)間無明顯差異。4.中藥外敷治療方式可以引起皮膚的過敏反應(yīng),不注意保暖時(shí)還有發(fā)生感冒發(fā)燒的風(fēng)險(xiǎn),使用“溫通消腫外敷方”治療BCRL患者時(shí)皮膚過敏反應(yīng)(Ⅱ)發(fā)生率為7%,與安慰劑組比較未發(fā)現(xiàn)顯著性差異。與安慰劑相比,未發(fā)現(xiàn)“溫通消腫外敷方”治療BCRL患者時(shí)增加患者血常規(guī)、尿常規(guī)、便常規(guī)、肝腎功能、鉀鈉氯離子水平和心電圖等指標(biāo)的惡化風(fēng)險(xiǎn)。5.本研究未發(fā)現(xiàn)采用“溫通消腫外敷方”治療BCRL的臨床有效率高于安慰劑,但不能以此簡單的否定“溫通消腫外敷方”的臨床功效,因?yàn)楸狙芯康慕Y(jié)果只能限于本次研究設(shè)計(jì)而言,如患者的入組方式、療程、課題資金支持力度、患者樣本量、患者依從性等方面,不能推廣到所有的患者,本研究結(jié)論還需要在今后升級版的高級別臨床試驗(yàn)中進(jìn)一步證實(shí)。
[Abstract]:[background] breast cancer postoperative upper limb edema (Breast cancer related lymphedema, BCRL) is one of the common complications after operation of breast cancer patient, often accompanied by many symptoms, there is still no cure, and the risk with lifelong disease, patients with BCRL in the body, the spirit bear great pain and decreased the quality of life of patients with breast cancer incidence increased in recent years, the 5 year survival rate improvement, BCRL has become after breast cancer patients a thorny problem. Effective means of modern medicine in the treatment of BCRL is very limited, the advocate the use of physical therapy, the effective rate of treatment is not ideal the traditional Chinese medicine. The treatment of BCRL reported more, whether oral or external treatment, the effective rate of treatment in 80-100% generally, traditional Chinese medicine and Western medicine treatment were significantly different. Compared with Pubmed and CNKI library after the discovery, though Chinese medicine treatment of BCRL Chinese reported more, but the drawback is that these conclusions lack of high-level evidence-based support, only for the review of cases analysis or simple cases; while on Pubmed, there are still no reports on Chinese medicine for the treatment of BCRL. Therefore, the design of a clinical trial of a higher level of evidence based medicine to verify the clinical curative effect of traditional Chinese medicine in the treatment of BCRL, will help to improve the current treatment of BCRL, better play the advantages of Chinese medicine. Previous research on TCM syndrome in patients after breast cancer surgery, we found that warming yang as the main treatment is the main treatment for breast cancer after operation method, on the basis of this, "Wen Yang Qi, and water swelling" method by "Wen Tong swelling external application", a randomized, double-blind, placebo-controlled, multi center clinical study design for BCRL, to look through the senior Don't be clinical trials of Chinese medicine treatment of BCRL to the world. The purpose of the study is to investigate the]1. warming detumescence clinical curative effect of the treatment of external application of "BCRL"; safety. Methods 2. evaluation "Wen Tong swelling external application of" treating BCRL this topic using prospective randomized, double-blind, placebo parallel control, clinical study design multi center, supported by the party and accept the Beijing Municipal Science and Technology Commission appointed Beijing Qihuang clinical research center of medicine of process monitoring. To determine the final research program in a number of demonstration program, complete the preparatory work before the patients were recruited, including through the ethical review of four research centers, international clinical trial registration, training centers and four researchers coordination, drug procurement, preparation room based on evidence-based medical center preset blind end of the preparation of the medicine concentrated decoction (test drug and placebo drugs). Then according to the standard set of recruited patients with BCRL. Check into the group, including upper extremity arteriovenous ultrasound, axillary lymph node B, blood routine, urine routine, stool routine, liver and kidney function and electrolytes examination. Patients according to the group order for each center has been previously blinded, the treatment of patients with 0,3,5,7,14, arm circumference records, and fill in the upper limb function evaluation scale (DASH) and the adverse reactions were recorded. Patients completed a check after the end of treatment group (with the same examination group) after the group, and according to the willingness to receive a free 14 day "Wen Tong swelling external party" really medicine to treatment. All cases of data entry by evidence-based medicine center lock the data in evidence-based medicine. Qihuang inspectors and responsible for the issue of three party presence unblinded, analysis of statistical data. Finally, the clear "Wen Tong swelling external application of clinical efficacy in the treatment of BCRL, and the safety evaluation was carried out. The results of the]1. study topic from start to implement the After Unblinding, completed under strict quality control, accord with the standard of quality control. The quality control content of the whole project is expected to complete the project include: ethical review, evidence based medicine center for the blind blind drug, unified procurement and quality control, design of drug preparation room preparation process, international clinical trial registration, researchers training the patients were recruited, third party, monthly quality supervision, evidence-based medicine data management, standardized quality control to complete the above unblinded. To ensure the accuracy and authenticity of the data subject.2. this topic according to the requirements of the recruitment of 96 patients with BCRL were enrolled, which lasted 18 months, among which 4 patients withdrew from the study due to adverse reactions, 8 patients lost off, a total of 84 patients completed the study, 14 days for a course. The baseline analysis shows the test drug and placebo groups in the age of patients, surgical breast cancer and axillary lymph node metastasis situation, in the history of drug allergy The history of Western medicine treatment, clinical stage, edema grading of no significant difference (P0.05), group of two groups of arm circumference measured value and DASH score showed no significant difference (P0.05), the group of two groups of patients in blood routine examination, urine routine, stool routine, liver and kidney function, no significant difference between the electrolyte level the electrocardiogram (P0.05) and other aspects. In conclusion, BCRL in the two groups were comparable in the baseline group, consistent with the random design of.3. according to the standard set by the topic of clinical effective, 39 cases of patients in the trial group of 20 cases for clinical effective rate was 51.3%; 45 cases of patients in the placebo group in 31 cases effective. Efficiency is 68.9%, the efficiency of the two groups no significant difference (P=0.12). Four stratified analysis center efficiency were 55.6%, 50%, 72.7% and 27.3%, there was no significant difference between the center (P0.05). After deducting the center effect, drug test group and placebo group effective rate are not significant According to the design data set. The difference analysis results are still invariant.4. secondary outcomes analysis found that with the prolongation of treatment time, observation index (arm circumference and upper extremity DASH score) continue to improve, but the change of DASH score as arm circumference changes. No obvious difference was observed before and after treatment the changes in the test group and the placebo group (Z=-0.94 P=0.35, and Z=-1.81, P=0.07); the upper limb function improved survival analysis found that the placebo group reached the clinical effective standard about in the 6.23 days, the test drug group reached the upper limb function DASH standard requires an average of 7.26 days, two groups of patients achieved no significant difference between the clinical effective time (P=0.37).5. test the medicine group found 3 cases of patients with skin allergic reactions, the incidence of adverse reaction was 7%, in addition to the test drug group found 1 cases of patients with cold have a fever; the placebo group found no adverse reactions to suspend Treatment of the patients. The incidence of adverse drug reaction test group skin, compared with placebo group found no significant difference (P=0.11). After the treatment of blood routine, urine routine, stool routine, liver and kidney function, abnormal potassium sodium chloride levels and electrocardiogram showed no significant difference in the two groups (P0.05) based. Conclusion]1. in the full argument on the completion of the randomized, double-blind, placebo-controlled, multi center clinical research design, project implementation process is rigorous, strict supervision, high levels of evidence for evidence-based medicine, the primary outcome of real.2. conclusion analysis, guidance and theory under the warm external application can improve the breast after the operation of carcinoma of upper limb edema clinical efficiency, temperature and external application of clinical swelling and placebo treatment had no significant difference between the BCRL efficiency, Wen Tong has no external application of swelling treatment of.3. secondary outcomes Found that temperature through external application of swelling and placebo can improve limb function and upper arm circumference, arm circumference as DASH score change but changes significantly, no significant difference between the improvement degree of two indexes between the experimental drug and placebo groups. Two groups of patients with upper extremity allergic reaction function to improve the time needed to reach the effective standard no difference.4. traditional Chinese medicine treatment mode can cause the skin, do not pay attention to keep warm when there is risk of a cold have a fever, "Wen Tong swelling external party" in the treatment of BCRL patients with skin allergic reaction (II) the incidence rate was 7%, compared with placebo group found no significant differences. Compared with placebo, found no warming swelling external application of "treating BCRL patients is increased in patients with blood routine, urine routine, stool routine, liver and kidney function, the risk of deterioration of.5. potassium sodium chloride levels and electrocardiogram index has not found in this study by" Wen Tong Xiao Swollen external party "in the treatment of BCRL clinical efficiency is higher than that of placebo, clinical efficacy but denied" not as a simple external application of swelling of Wen Tong ", because the results of this study can only be limited to the study design, such as into the group of patients, treatment, subject to financial support, with the sample size, patient compliance so, can not be extended to all of the patients, the conclusions of this study are needed in the future upgrade of the high level in clinical trials is further confirmed.

【學(xué)位授予單位】：北京中醫(yī)藥大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R737.9

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