Methodological study on N-of-1 trials of traditional Chinese medicine based on bronchiectasis_Chinese Journal of Evidence-Based Medicine

Authors：

CHEN Huijia ^1,2 ,  HUANG Haiyin ¹ , WANG Zhenwei ¹ , YANG Peilan ¹ , WU Yingen ³ , XU Minhua ¹ , ZHANG Yi ¹ , TANG Jie ¹ , WANG Mingli ¹ , LU Lizhi ¹ , AN Jiaqi ¹ , NIAN Hua ⁴ , SHEN Lihua ⁴

1. Department of Respiratory Disease, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P. R. China;
2. Department of Traditional Chinese Medicine, Minhang Hospital, Fudan University, Shanghai 201199, P. R. China;
3. Department of Respiratory Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P. R. China;
4. Department of Pharmacy, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P. R. China;

Corresponding?author：

HUANG Haiyin, Email: haiyin_huang@126.com

Keywords：

N-of-1 trials; Bronchiectasis; Carryover effects; Syndrome differentiation; Traditional Chinese medicine

DOI：

10.7507/1672-2531.202407146

Video：

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Objective A series of N-of-1 trials were conducted to evaluate the effects of traditional Chinese medicine (TCM) individualized syndrome differentiation on stable bronchiectasis, and to explore a clinical trial method that is consistent with the characteristics of TCM. Methods The original plan consisted of 3 cycles, with each cycle consisting of two observation periods: experimental and control. Take the medication for 3 weeks each period and then stop for 1 week. Because the results were not as expected, another cycle of trials was added (a total of 4 cycles). The trial period was treated with individualized syndrome differentiation prescription and the control period was treated with placebo. The outcome measures were Likert scale score of general symptoms (primary outcome), Likert scale score of respiratory symptoms, CAT score, 24h sputum volume and TCM symptom score. Data analysis (including residual effects and stage effects analysis) used group-designed independent sample t tests, paired t tests or non-parametric tests, mixed effects models, and Bayesian analysis. Results A total of 31 participants were formally enrolled, with 24 completing all four cycles. Independent sample t-tests and mixed-effects models showed no significant period or carryover effects. Bayesian analysis showed that there were residual effects on some outcome measures of some individuals. Six participants showed statistically significant differences in overall symptom Likert scale scores (P<0.05). Bayesian analysis found that TCM was more effective than placebo in more individuals. No significant differences were found between individualized TCM and placebo at the group level for any of the outcome measures. Conclusion This study method highly simulates the clinical practice of TCM, with good operability and patient compliance, and has no obvious residual effect of TCM on the whole, which can provide the best individualized evidence-based medicine evidence of short-term efficacy of TCM. Bayesian analysis can improve the sensitivity of individual statistics.

Citation： CHEN Huijia, HUANG Haiyin, WANG Zhenwei, YANG Peilan, WU Yingen, XU Minhua, ZHANG Yi, TANG Jie, WANG Mingli, LU Lizhi, AN Jiaqi, NIAN Hua, SHEN Lihua. Methodological study on N-of-1 trials of traditional Chinese medicine based on bronchiectasis. Chinese Journal of Evidence-Based Medicine, 2025, 25(3): 319-328. doi: 10.7507/1672-2531.202407146 Copy

1.	莊銘, 安佳麗, 鐘夢媛, 等. 中醫藥臨床療效評價方法研究進展. 中國中藥雜志, 2023, 48(12): 3263-3268.
2.	Kravitz RL, Duan N, Braslow J. Evidence-based medicine, heterogeneity of treatment effects, and the trouble with averages. Milbank Q, 2004, 82(4): 661-687.
3.	Guyatt G, Sackett D, Taylor DW, et al. Determining optimal therapy--randomized trials in individual patients. N Engl J Med, 1986, 314(14): 889-892.
4.	Duan N, Kravitz RL, Schmid CH. Single-patient (n-of-1) trials: a pragmatic clinical decision methodology for patient-centered comparative effectiveness research. J Clin Epidemiol, 2013, 66(8 Suppl): S21-S28.
5.	張賀, 李秋憶, 樊懿萱, 等. 單病例隨機對照試驗在中醫藥臨床研究中的探索與思考. 中西醫結合心腦血管病雜志, 2020, 18(18): 2945-2947, 2954.
6.	OCEBM Levels of Evidence Working Group. The Oxford levels of evidence 2. Oxford: Oxford Centre for Evidence-based Medicine.
7.	王明莉, 王振偉, 陳新林, 等. 單病例試驗的方法學比較和臨床應用探索. 中國循證醫學雜志, 2022, 22(4): 468-474.
8.	陳繪佳, 王振偉, 張誼, 等. 針對“殘留效應”混合效應模型的辨證論治方治療支氣管擴張癥的單病例隨機對照試驗. 中國循證醫學雜志, 2023, 23(5): 504-512.
9.	成人支氣管擴張癥診治專家共識編寫組. 成人支氣管擴張癥診治專家共識. 中華結核和呼吸雜志, 2012, 35(7): 485-492.
10.	黃海茵, 楊佩蘭, 湯杰, 等. 扶正化痰清熱法治療支氣管擴張癥46例遠期療效觀察. 中醫雜志, 2012, 53(10): 848-852.
11.	中華中醫藥學會. 中醫內科常見病診療指南中醫病證部分. 北京: 中國中醫藥出版社, 2008.
12.	李建生, 王至婉, 謝洋, 等. 支氣管擴張癥中醫證候診斷標準(2019版). 中醫雜志, 2020, 61(15): 1377-1380.
13.	陳敏, 黃寧靜, 王祎晟. 瀉火止痛方治療肝火上炎型偏頭痛的臨床研究. 中西醫結合心腦血管病雜志, 2015, 13(12): 1375-1377.
14.	Guyatt G, Rennie D. Users' guides to the medical literature: essentials of evidence-based clinical practice (2nd edition). Chicago: American Medical Association Press, 2002.
15.	Guyatt GH, Keller JL, Jaeschke R, et al. The n-of-1 randomized controlled trial: clinical usefulness. Our three-year experience. Ann Intern Med, 1990, 112(4): 293-299.
16.	Lee BY, Lee S, Lee JS, et al. Validity and reliability of CAT and dyspnea-12 in bronchiectasis and tuberculous destroyed lung. Tuberc Respir Dis (Seoul), 2012, 72(6): 467-474.
17.	鄭筱萸. 中藥新藥臨床研究指導原則. 北京: 中國醫藥科技出版社, 2002.
18.	Vohra S, Shamseer L, Sampson M, et al. CONSORT extension for reporting N-of-1 trials (CENT) 2015 statement. BMJ, 2015, 350: h1738.
19.	Li J, Hu JY, Zhai JB, et al. CONSORT extension for reporting N-of-1 trials for traditional Chinese medicine (CENT for TCM): recommendations, explanation and elaboration. Complement Ther Med, 2019, 46: 180-188.
20.	Lu L, An J, Chen H, et al. A series of n-of-1 trials for traditional Chinese medicine using a Bayesian method: study rationale and protocol. Evid Based Complement Alternat Med, 2021, 2021: 9976770.
21.	Chen KW, Chow SC, Li G. A note on sample size determination for bioequivalence studies with high-order crossover designs. J Pharmacokinet Biopharm, 1997, 25(6): 753-765.
22.	Bacchetti P, Leung JM. Sample size calculations in clinical research. Anesthesiology, 2002, 97(4): 1028-1029.
23.	Porcino AJ, Shamseer L, Chan AW, et al. SPIRIT extension and elaboration for n-of-1 trials: SPENT 2019 checklist. BMJ, 2020, 368: m122.
24.	Grieve AP, Senn S. Cross-over trials in clinical research. J R Sta So, 1994, 43(3): 469.
25.	劉玉, 黃彬, 陳生, 等. 六味地黃膠囊治療肝腎陰虛證療效評價的例隨機對照雙盲試驗. 中醫雜志, 2018, 59(11): 947-951.
26.	孫振球. 醫學統計學(第4版). 北京: 人民衛生出版社, 2014.
27.	Zucker DR, Ruthazer R, Schmid CH. Individual (N-of-1) trials can be combined to give population comparative treatment effect estimates: methodologic considerations. J Clin Epidemiol, 2010, 63(12): 1312-1323.
28.	陳新林, 劉鳳斌, 趙菲, 等. 探索適合中醫藥N-of-1試驗的設計方案及模型. 廣州中醫藥大學學報, 2018, 35(1): 172-175.
29.	陳新林, 陳麗霞, 黃海茵, 等. 系列N-of-1試驗定量數據混合效應模型的模擬研究. 中國循證醫學雜志, 2021, 21(6): 689-695.
30.	Nikles J, Mitchell G, McKinlay L, et al. A series of n-of-1 trials of stimulants in brain injured children. NeuroRehabilitation, 2017, 40(1): 11-21.
31.	Stunnenberg BC, Raaphorst J, Groenewoud HM, et al. Effect of mexiletine on muscle stiffness in patients with nondystrophic myotonia evaluated using aggregated n-of-1 trials. JAMA, 2018, 320(22): 2344-2353.
32.	Huang H, An J, Lu L, et al. Methodological considerations in n-of-1 trials of traditional Chinese medicine. Evid Based Complement Alternat Med, 2021, 2021: 6634134.
33.	Yuhong H, Qian L, Yu L, et al. An n-of-1 trial service in clinical practice: testing the effectiveness of Liuwei Dihuang decoction for kidney-yin deficiency syndrome. Evid Based Complement Alternat Med, 2013, 2013: 827915.
34.	Xie T, Yu Z. N-of-1 design and its applications to personalized treatment studies. Stat Biosci, 2017, 9(2): 662-675.
35.	翟靜波, 商洪才. 基于貝葉斯單病例試驗的中醫個體化療效動態評價方法. 中國循證醫學雜志, 2023, 23(11): 1334-1339.
36.	張迪, 雒琳, 文天才, 等. 中醫辨證論治療效評價研究進展. 科技導報, 2023, 41(14): 32-41.
37.	Huang H, Yang P, Wang J, et al. Investigation into the individualized treatment of traditional Chinese medicine through a series of N-of-1 trials. Evid Based Complement Alternat Med, 2018, 2018: 5813767.
38.	Zi S, Huang H, Yang P, et al. Evaluating the effects of heat-clearing traditional Chinese medicine in stable bronchiectasis by a series of N-of-1 trials. Evid Based Complement Alternat Med, 2022, 2022: 6690638.
39.	朱春勝, 聶安政, 王笑, 等. 中藥量效關系的研究進展. 中草藥, 2019, 50(7): 1708-1712.
40.	劉克峰, 魏曉東. 中藥湯劑當用生半夏. 中醫臨床研究, 2015, 7(18): 139-140.
41.	楊俊杰, 李金平, 卞華. 生半夏毒性作用機制和臨床應用探討. 醫學爭鳴, 2021, 12(3): 33-36.

1. 莊銘, 安佳麗, 鐘夢媛, 等. 中醫藥臨床療效評價方法研究進展. 中國中藥雜志, 2023, 48(12): 3263-3268.
2. Kravitz RL, Duan N, Braslow J. Evidence-based medicine, heterogeneity of treatment effects, and the trouble with averages. Milbank Q, 2004, 82(4): 661-687.
3. Guyatt G, Sackett D, Taylor DW, et al. Determining optimal therapy--randomized trials in individual patients. N Engl J Med, 1986, 314(14): 889-892.
4. Duan N, Kravitz RL, Schmid CH. Single-patient (n-of-1) trials: a pragmatic clinical decision methodology for patient-centered comparative effectiveness research. J Clin Epidemiol, 2013, 66(8 Suppl): S21-S28.
5. 張賀, 李秋憶, 樊懿萱, 等. 單病例隨機對照試驗在中醫藥臨床研究中的探索與思考. 中西醫結合心腦血管病雜志, 2020, 18(18): 2945-2947, 2954.
6. OCEBM Levels of Evidence Working Group. The Oxford levels of evidence 2. Oxford: Oxford Centre for Evidence-based Medicine.
7. 王明莉, 王振偉, 陳新林, 等. 單病例試驗的方法學比較和臨床應用探索. 中國循證醫學雜志, 2022, 22(4): 468-474.
8. 陳繪佳, 王振偉, 張誼, 等. 針對“殘留效應”混合效應模型的辨證論治方治療支氣管擴張癥的單病例隨機對照試驗. 中國循證醫學雜志, 2023, 23(5): 504-512.
9. 成人支氣管擴張癥診治專家共識編寫組. 成人支氣管擴張癥診治專家共識. 中華結核和呼吸雜志, 2012, 35(7): 485-492.
10. 黃海茵, 楊佩蘭, 湯杰, 等. 扶正化痰清熱法治療支氣管擴張癥46例遠期療效觀察. 中醫雜志, 2012, 53(10): 848-852.
11. 中華中醫藥學會. 中醫內科常見病診療指南中醫病證部分. 北京: 中國中醫藥出版社, 2008.
12. 李建生, 王至婉, 謝洋, 等. 支氣管擴張癥中醫證候診斷標準(2019版). 中醫雜志, 2020, 61(15): 1377-1380.
13. 陳敏, 黃寧靜, 王祎晟. 瀉火止痛方治療肝火上炎型偏頭痛的臨床研究. 中西醫結合心腦血管病雜志, 2015, 13(12): 1375-1377.
14. Guyatt G, Rennie D. Users' guides to the medical literature: essentials of evidence-based clinical practice (2nd edition). Chicago: American Medical Association Press, 2002.
15. Guyatt GH, Keller JL, Jaeschke R, et al. The n-of-1 randomized controlled trial: clinical usefulness. Our three-year experience. Ann Intern Med, 1990, 112(4): 293-299.
16. Lee BY, Lee S, Lee JS, et al. Validity and reliability of CAT and dyspnea-12 in bronchiectasis and tuberculous destroyed lung. Tuberc Respir Dis (Seoul), 2012, 72(6): 467-474.
17. 鄭筱萸. 中藥新藥臨床研究指導原則. 北京: 中國醫藥科技出版社, 2002.
18. Vohra S, Shamseer L, Sampson M, et al. CONSORT extension for reporting N-of-1 trials (CENT) 2015 statement. BMJ, 2015, 350: h1738.
19. Li J, Hu JY, Zhai JB, et al. CONSORT extension for reporting N-of-1 trials for traditional Chinese medicine (CENT for TCM): recommendations, explanation and elaboration. Complement Ther Med, 2019, 46: 180-188.
20. Lu L, An J, Chen H, et al. A series of n-of-1 trials for traditional Chinese medicine using a Bayesian method: study rationale and protocol. Evid Based Complement Alternat Med, 2021, 2021: 9976770.
21. Chen KW, Chow SC, Li G. A note on sample size determination for bioequivalence studies with high-order crossover designs. J Pharmacokinet Biopharm, 1997, 25(6): 753-765.
22. Bacchetti P, Leung JM. Sample size calculations in clinical research. Anesthesiology, 2002, 97(4): 1028-1029.
23. Porcino AJ, Shamseer L, Chan AW, et al. SPIRIT extension and elaboration for n-of-1 trials: SPENT 2019 checklist. BMJ, 2020, 368: m122.
24. Grieve AP, Senn S. Cross-over trials in clinical research. J R Sta So, 1994, 43(3): 469.
25. 劉玉, 黃彬, 陳生, 等. 六味地黃膠囊治療肝腎陰虛證療效評價的例隨機對照雙盲試驗. 中醫雜志, 2018, 59(11): 947-951.
26. 孫振球. 醫學統計學(第4版). 北京: 人民衛生出版社, 2014.
27. Zucker DR, Ruthazer R, Schmid CH. Individual (N-of-1) trials can be combined to give population comparative treatment effect estimates: methodologic considerations. J Clin Epidemiol, 2010, 63(12): 1312-1323.
28. 陳新林, 劉鳳斌, 趙菲, 等. 探索適合中醫藥N-of-1試驗的設計方案及模型. 廣州中醫藥大學學報, 2018, 35(1): 172-175.
29. 陳新林, 陳麗霞, 黃海茵, 等. 系列N-of-1試驗定量數據混合效應模型的模擬研究. 中國循證醫學雜志, 2021, 21(6): 689-695.
30. Nikles J, Mitchell G, McKinlay L, et al. A series of n-of-1 trials of stimulants in brain injured children. NeuroRehabilitation, 2017, 40(1): 11-21.
31. Stunnenberg BC, Raaphorst J, Groenewoud HM, et al. Effect of mexiletine on muscle stiffness in patients with nondystrophic myotonia evaluated using aggregated n-of-1 trials. JAMA, 2018, 320(22): 2344-2353.
32. Huang H, An J, Lu L, et al. Methodological considerations in n-of-1 trials of traditional Chinese medicine. Evid Based Complement Alternat Med, 2021, 2021: 6634134.
33. Yuhong H, Qian L, Yu L, et al. An n-of-1 trial service in clinical practice: testing the effectiveness of Liuwei Dihuang decoction for kidney-yin deficiency syndrome. Evid Based Complement Alternat Med, 2013, 2013: 827915.
34. Xie T, Yu Z. N-of-1 design and its applications to personalized treatment studies. Stat Biosci, 2017, 9(2): 662-675.
35. 翟靜波, 商洪才. 基于貝葉斯單病例試驗的中醫個體化療效動態評價方法. 中國循證醫學雜志, 2023, 23(11): 1334-1339.
36. 張迪, 雒琳, 文天才, 等. 中醫辨證論治療效評價研究進展. 科技導報, 2023, 41(14): 32-41.
37. Huang H, Yang P, Wang J, et al. Investigation into the individualized treatment of traditional Chinese medicine through a series of N-of-1 trials. Evid Based Complement Alternat Med, 2018, 2018: 5813767.
38. Zi S, Huang H, Yang P, et al. Evaluating the effects of heat-clearing traditional Chinese medicine in stable bronchiectasis by a series of N-of-1 trials. Evid Based Complement Alternat Med, 2022, 2022: 6690638.
39. 朱春勝, 聶安政, 王笑, 等. 中藥量效關系的研究進展. 中草藥, 2019, 50(7): 1708-1712.
40. 劉克峰, 魏曉東. 中藥湯劑當用生半夏. 中醫臨床研究, 2015, 7(18): 139-140.
41. 楊俊杰, 李金平, 卞華. 生半夏毒性作用機制和臨床應用探討. 醫學爭鳴, 2021, 12(3): 33-36.

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Methodological study on N-of-1 trials of traditional Chinese medicine based on bronchiectasis

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