Assessment of therapeutic effects of TMN-1 and DHJST on menopausal symptoms and osteoarthritis

本計劃之目標為由台大公共衛生學院成立監測中心，採多中心主動監測系統追蹤、監測下，探討台更一號治療更年期症候群及獨活寄生湯之臨床療效與安全性。中藥複方台更一號研究的主要療效指標為Kupperman index score第0、4週與12週追蹤評估量表之分數變化，次要指標為世界衛生組織生活品質量表台灣簡明版( WHOQOL-BREF Taiwan version )在第0、4週與12週之分數變化；獨活寄生湯研究的主要療效指標為Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)及疼痛視覺評估量表，第0、2週與4週追蹤評估量表之分數變化，次要指標為WHOQOL-BREF Taiwan version 及中醫證型問卷在第0、2週與4週之分數變化。至於安全性的評估上，則主動觀察受試個案在研究期間所出現的不良事件，並進一步評估不良事件與研究藥物間的因果關係。 中藥複方台更一號研究依個案納入/排除條件共收納143位受試者，共126位受試者進入試驗的藥物擴清期 (0-2週)，並接受用藥前的臨床評估(基礎值，含身體檢查、生命徵象、Kupperman index、WHOQOL-BREF Taiwan version、實驗室數值檢測等)，之後則開始服用12週的研究藥物，每天三次，每次4公克；期間亦分別於服藥後的1、2、3、4、6、8、10、12 週回診，最後共有103位受試者完成期末評估。獨活寄生湯研究依個案納入/排除條件共收納69位受試者，共69位受試者進入試驗的藥物擴清期 (0-2週)，並接受用藥前的臨床評估(基礎值，含身體檢查、生命徵象、WOMAC index、WHOQOL-BREF Taiwan version、實驗室數值檢測等)，之後則開始服用4週的研究藥物，每天二次，每次2.5公克；期間亦分別於服藥後的2、4 週回診，最後共有68受試者完成期末評估。每位受試者皆充分了解本研究之目的及內容，簽署知情同意書後，並於每次回診接受各項療效與安全性指標的評值，由各參與醫院之專職研究護士，依研究標準作業流程 (Standard Operation Procedure)，執行主動之監測。 中藥複方台更一號研究以12週追蹤之103位更年期婦女而言，更年期症候群及生活品質分數有進步。主要指標 Kupperman index score其4週與12週追蹤的前後差異性有統計上顯著之差異。次要指標WHOQOL-BREF Taiwan version其12週追蹤的前後差異性不顯著。以4週追蹤之68退化性膝關節病人而言，膝關節疼痛、僵硬及功能分數在獨活寄生湯治療2與4週後有統計上顯著之改善。然而傳統辨別獨活寄生湯適用的症狀及證型如腰膝痠軟及畏惡風寒，及次要指標WHOQOL-BREF Taiwan version其2與4週追蹤的前後差異性不顯著。在安全性上，中藥複方台更一號其所發生的不良反應嚴重度多屬於輕微至中度，僅有5件顯示與研究藥物具「極有可能」的相關性-分別是噁心 (1件)，腹瀉 (2件)，胃悶脹痛 (1件)及腹脹 (1件)，且並不影響受試者生活功能。獨活寄生湯的不良反應亦僅有4件顯示與研究藥物具「極有可能」的相關性-分別是心悸、皮膚白斑、臉潮紅及腹瀉各1件。研究結果顯示：台更1號在治療更年期症候群上，獨活寄生湯在治療退化性膝關節上，除了具有不錯的療效外，亦相當的安全。 總而言之，採主動監測系統的追蹤觀察研究法，可清楚的釐清台更1號及獨活寄生湯的藥物安全的因果關係，當然透過此研究法，我們驗證了台更1號及獨活寄生湯，分別在更年期症候群及退化性膝關節上，可能有效的適應症及群族，提供了古籍未曾記載的實證資料。Context: There is a paucity of data supporting the efficacy of herbal medicines in treating both menopausal symptoms and osteoarthritis in knee. Objective: One is to evaluate safety and efficacy of the finished Chinese herbal product TMN-1 in the treatment of menopausal symptoms in climacteric women. Second is to evaluate both the safety and efficacy of the finished Chinese herbal product, DU-HUO-JI-SHENG-TANG, in reducing the symptoms of degenerative osteoarthritis (OA) of the knee. Design and Setting: Two prospective, observational follow-up studies were carried out. TMN-1 trial was conducted in 4 hospitals in Taiwan between July 2003 and December 2004. DHJST trial was conducted in two hospitals in Taipei between April and October 2005. Participants: TMN-1 trial : Initially 126 women were included who were between 45 and 55 years of age, were experiencing hot flashes, and were without hormone replacement therapy. Women were excluded if they had any signs of active cancer. Of the participants, 82% completed the study. The reasons for withdrawal included adverse effects (n = 7), failed to return (n = 7), lack of efficacy (n = 6), and from protocol deviation (n = 3). DHJST trial : Initially 87 subjects sought for medical help were screened. 69 of them were diagnosed as a degenerative OA of the knee through roentgenography diagnosed by radiologists. After the collection of baseline data, 1 of them failed to return for lack of efficacy, while the rest completed the study. Intervention: TMN-1 trial : Every participant received TMN-1 treatment 4 gm, 3 times per day, for 12 weeks. DHJST trial : Each of the sample participants received DU-HUO-JI-SHENG-TANG treatment at a rate of 2.5 gm, twice per day, for four weeks. Main Outcome Measure: TMN-1 trial : Primary measures were change in frequency of hot flashes and severity of menopausal symptoms measured by Kupperman Index (KI). Secondary outcomes included changes in quality of life and adverse events. DHJST trial : Baseline scores were measured on the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC), followed by further measures at the end of weeks 1, 2 and 4. The World Health Organization Quality of Life (WHOQOL) assessment was undertaken as a secondary outcome, with pattern identification (bian zheng) questionnaires being adopted and adverse events also being measured. Multivariate regression models were constructed to explore the differences between the WOMAC and WHOQOL scores at weeks 2 and 4, self-compared with the baseline by various determinants, including age, gender, body mass index, severity at baseline, use of rescue medication, aversion to cold and flaccidity of the lower back and knees. Results: TMN-1 trial : Significant improvement in scores of hot flashes and KI at weeks 4 and 12 in the 50 peri- and 53 postmenopausal women who completed this study (p<0.001). Logistic regression analyses showed that perimenopausal women with hot flashes had sevenfold (95% confidence interval [CI], 1.8 to 28.0) odds of improvement in favor of treatment, whereas that of the postmenopausal group was 1.5 (95% CI, 0.5 to 4.2). Further analyses showed that TMN-1 produced superior benefit in women with moderate and severe menopausal symptoms (KI >=21), compared with those with mild symptoms. It also improved symptoms of insomnia, nervousness, melancholia, and palpitation in perimenopausal women. Five adverse drug reactions were detected: three single events of nausea, abdominal pain, and abdominal fullness, and 2 events of diarrhea. DHJST trial : Amongst the 68 participants, there were statistically-significant reductions in WOMAC scores for pain, stiffness and physical functioning in the second and fourth weeks, with the effects first appearing during week 2. By week 4, the mean WOMAC scores had fallen from 22.2 to 16.1 for pain, from 28.1 to 18.5 for stiffness, and from 22.6 to 18.2 for physical functioning, whilst the global score for pain under the ‘visual analogue scale’ (VAS) was reduced from 38.7 to 27.8. The results indicate that the magnitudes of the reductions in the above symptoms were associated with the baseline severity of the symptoms. Contrary to the hypotheses proposed in an ancient text on traditional Chinese medicine, there were no significant effects on flaccidity of the lower back and knees, or aversion to cold. There was also no significant change in either the WHOQOL assessment or the pattern difference based upon traditional theory. There were only four adverse drug reactions judged to be potentially related to the treatment, involving single events of skin discoloration, flashes, diarrhea and tachycardia. Conclusion: TMN-1 trial : This study provides evidence that 12 weeks of TMN-1 therapy is a viable alternative treatment to consider in perimenopausal women with hot flashes, particularly in those with palpitation, emotional disturbance, and insomnia. DHJST trial : For degenerative OA of knee, four-week therapy with the Chinese herbal products DU-HUO-JI-SHENG-TANG seemed to be ineffective in treating flaccidity or aversion to cold, but appeared both to reduce pain and stiffness, and to improve physical function. In conclusion, observational studies have specific advantages in studying aspects of clinical safety. The use of such studies to prove efficacy is limited because bias in patient selection may occur. However, the results we found from this kind of studies can provide more precious information to verify whether it is a potential treatment or not to symptom relief during climacteric period or symptomatic knee in patients with OA. Nevertheless, the level of evidence on efficacy of both TMN-1 and DHJST can be significantly increased by well-designed double blind randomized studies.摘要....................................................6 第一章、總論...........................................12 （一）中藥臨床療效評估.................................12 （二）更年期與生活品質相關之研究.......................14 （三）更年期潮熱與治療相關之研究.......................16 （四）退化性膝關節炎與治療相關之研究...................18 （五）未來研究的建議...................................20 第二章、影響更年期婦女生活品質之預測因子...............28 第三章、治療更年期症候群之中藥複方療效及安全性主動監測研究.......51 第四章、獨活寄生湯治療退化性膝關節炎之療效及安全性主動監測研究.....7