Current Status of N-of-1 Trials for Herbal Medicine -Literature Review

Chang-woon Jeung; Sun-woo Jeon; Hee-Geun Jo; Jeung, Chang-woon; Jeon, Sun-woo; Jo, Hee-Geun

doi:10.13048/jkm.20008

JKM > Volume 41(1); 2020 > Article

Jeung, Jeon, and Jo: Current Status of N-of-1 Trials for Herbal Medicine -Literature Review

Review Article

The Journal of Korean Medicine 2020; 41(1): 107-116.

Published online: March 9, 2020

DOI: https://doi.org/10.13048/jkm.20008

Current Status of N-of-1 Trials for Herbal Medicine -Literature Review

Chang-woon Jeung

, Sun-woo Jeon

, Hee-Geun Jo^*

Chung-Yeon Central Institute

Correspondence to: Hee-Geun Jo, Chung-Yeon Central Institute, 64 Sangmujungang-ro, Seo-gu, Gwangju 61949, Korea, Tel: +82-62-371-1075, Fax: +82-62-371-1074, E-mail: jho3366@hanmail.net

Received January 16, 2020 Revised February 27, 2020 Accepted February 28, 2020

Abstract

Objectives

To overcome the limitations of randomized controlled trials, many other trials design is tested. The n-of-1 trial is a promising research method in the field of Korean medicine because of this methodology can examine the optimal treatment for each patient strictly. Therefore, we reviewed the status of N-of-1 studies on herbal medicine.

Methods

A systematic literature review was conducted based on the pubmed database. The search term were ‘N-of-1 Trial’, ‘Chinese Medicine’, ‘Herbal Medicine’, ‘Kampo’. There was no restriction in year.

Results

Four clinical trials have been identified to demonstrate the effectiveness of herbal medicines for Kidney-yin-deficiency syndrome, bronchiectasis and gastric cancer. These studies suggest that the N-of-1 design is a study that encourages patient involvement, demonstrates the effectiveness of herbal medicines and helps reduce unnecessary medication.

Conclusion

The N-of-1 clinical trial may be a rigorous methodology suitable for the clinical setting and may help the development of evidence-based Korean medicine. Attention is also needed in this research method in Korea.

Keywords: N-of-1, Single Case Studies, Clinical Trial, Herbal Medicine, Korean medicine

Fig. 1

ABAB design

Fig. 2

Flowchart of review

Table 1

Characteristics of N-of-1 Trials for Herbal Medicine

Citations	Target disease	Number of subjects	Research design	Inverventions	Controls	Evaluation Items	Outcome	Remarks
Yuhong H (2013) 18	Kidney-yin-deficiency syndrome	N=50	ABABAB (24week)	Liuweidihuang-wan	Placebo	Medication persistence, Kidney-yin-deficiency score, SF-36	There is no significant difference between Liuweidihuang-wan and placebo in patients with Kidney-yin-deficiency syndrome. Patients who responded clearly to Liuweidihuang-wan wanted to keep the medication.	This study shows Liuweidihuang-wan, a representative treatment for Kidney-yin-deficiency, has not been shown to be effective for all Kidney-yin-deficiency patients. However, this results may be due to the limitation of diagnosis through Kidney-yin-deficiency score,.
Huang H (2014) 19	Bronchiectasis	N=3	ABABAB (12–18 week)	In addition to the controls Lung-Spleen-Qi-Deficiency(肺脾氣虛) : Codonopsis pilosula(黨參), Pericarpium Citri Reticulatae(陳皮), Rhizoma Atractylodis Macrocephalae(朮) Qi-yin-deficiency(氣陰證) : Radix Adenophorae (南沙參), Radix Glehniae (北沙參), Radix Rehmanniae Recens (生地黃) Phleigm-heat(痰熱) : Scutellaria baicalensis(黃芩), Herba Violae(紫花地丁)	Radix Lithospermi (紫草) 15 g, Rhizoma Fagopyri Cymosi (金蕎麥) 30 g, Radix Ophiopogonis(麥門冬) 15 g, Poria cocos(茯苓) 15 g, Radix Astragali (黃芪) 20 g, Rhizoma Bletillae (白芨) 10 g, Platycodon grandiflorum (朮) 10 g, Semen Coicis (薏苡仁) 30 g.	Symptom score, expectoration volume.	Syndrome-differentiation based administration did not show any significant difference in patients with bronchiectasis.	These study shows that syndrome-differentiation based administration has statistically significant effects. These results may be due to the limitation of the syndrome-differentiation approach used in this study.
Huang H (2018) 20	Bronchiectasis	N=17	ABABAB Or ABAB (24week)			Symptom score, expectoration volume, COPD Assessment score(CAT)	In patients with bronchiectasis, syndrome-differentiation based administration showed a statistically significant but clinically insignificant effect compared to the controls. There was a clear statistical difference compared to the prior small study.
Li J (2019) 21	Gastric Cancer	N=6	ABABAB or ABAB 20–30 weeks)	In addition to the controls Astragalus mongholicus (黃芪) 120 g, Semen Cuscutae (菟絲子) 60 g	Radix Pseudostellariae (太子參) 45 g, Rhizoma Atractylodis Macrocephalae (朮) 45 g, Rhizoma Zingiberis (乾薑) 45 g, Radix Glycyrrhizae Preparata (炙甘草) 45 g, Rhizoma Pinellinae Praeparata (法半夏) 15 g, Fructus Amomi (砂仁) 15 g, Rhizoma Dioscoreae (山藥) 60 g, Lignum Millettiae (鷄血藤) 60 g.	WBC count, Quality of Life	Astragalus and Semen Cuscutae were able to improve white blood cell reduction by chemotherapy in gastric cancer.	These study shows that addition of Astragalus and Semen Cuscutae is effective on white blood cell reduction. However, results from fewer subjects are a limitation in generalizing results. It is necessary to identify which patients respond by this treatment.

참고문헌

1. Akobeng, AK. Understanding randomised controlled trials. Archives of Disease in Childhood, (2005). 90(8), 840-844.

2. Spieth, PM, Kubasch, AS, Penzlin, AI, Illigens, BM, Barlinn, K, & Siepmann, T. Randomized controlled trials - a matter of design. Neuropsychiatric Disease and Treatment, (2016). 12, 1341-9.

3. Suresh, K. An overview of randomization techniques: An unbiased assessment of outcome in clinical research. Journal of Human Reproductive Sciences, (2011). 4(1), 8-11.

4. Jones, DS, & Podolsky, SH. The history and fate of the gold standard. Lancet, (2015). 385(9977), 1502-3.

5. Chao, J, Dai, Y, Verpoorte, R, Lam, W, Cheng, YC, & Pao, LH, et al. Major achievements of evidence-based traditional Chinese medicine in treating major diseases. Biochemical Pharmacology, (2017). 139, 94-104.

6. Sackett, DL, Rosenberg, WM, & Gray, JA, et al. Evidence based medicine: what it is and what it isn’t. BMJ, (1996). 312(7023), 71-2.

7. Guyatt, G, Sackett, D, Taylor, DW, Chong, J, Roberts, R, & Pugsley, S. Determining optimal therapy--randomized trials in individual patients. The New England Journal of Medicine, (1986). 314(14), 889-92.

8. Guyatt, GH, Keller, JL, Jaeschke, R, Rosenbloom, D, Adachi, JD, & Newhouse, MT. The n-of-1 randomized controlled trial: clinical usefulness. Our three-year experience. Annals of Internal Medicine, (1990). 112(4), 293-9.

9. Shaffer, JA, Kronish, IM, Falzon, L, Cheung, YK, & Davidson, KW. N-of-1 Randomized Intervention Trials in Health Psychology: A Systematic Review and Methodology Critique. Annals of Behavioral Medicine, (2018). 52(9), 731-742.

10. Mirza, RD, Punja, S, Vohra, S, & Guyatt, G. The history and development of N-of-1 trials. Journal of the Royal Society of Medicine, (2017). 110(8), 330-340.

11. Lillie, EO, Patay, B, Diamant, J, Issell, B, Topol, EJ, & Schork, NJ. The n-of-1 clinical trial: the ultimate strategy for individualizing medicine? Personalized Medicine, (2011). 8(2), 161-173.

12. Schork, NJ. Personalized medicine: Time for one-person trials. Nature, (2015). 520(7549), 609-11.

13. Terasawa, K. Evidence-based Reconstruction of Kampo Medicine: Part-III-How Should Kampo be Evaluated? Evidence-Based Complementary and Alternative Medicine, (2004). 1(3), 219-222.

14. Li, J, Tian, J, Ma, B, & Yang, K. N-of-1 trials in China. Complementary Therapies in Medicine, (2013). 21(3), 190-4.

15. Yoshinaga, R, Goto, Y, Inoue, H, Yano, H, Nabeshima, S, & Tahara, E. A Case of Lower Back with Extremity Pain Successfully Treated with Kanzobushito. Kampo Medicine, (2019). 70(2), 146-150.

16. Tsubo, T, Unita, A, Furuta, T, Suzuki, M, Ueno, T, & Suzuki, T, et al. A Patient with Diffuse Panbronchiolitis Treated with a Combination of Keishikyoshakuyakukasokyoto and Acupuncture. Kampo Medicine, (2019). 70(2), 99-105.

17. Jeung, CW, Jeon, SW, & Kim, HK. Reduction of Adverse Effects from Jayeumganghwa-tang for Pegylated Liposomal Doxorubicin and Carboplatin in Recurrent Ovarian Cancer. The Journal of Internal Korean Medicine, (2019). 40(6), 1278-1287.

18. Yuhong, H, Qian, L, Yu, L, Yingqiang, Z, Yanfen, L, & Shujing, Y, et al. An n-of-1 Trial Service in Clinical Practice: Testing the Effectiveness of Liuwei Dihuang Decoction for Kidney-Yin Deficiency Syndrome. Evidence-Based Complementary and Alternative Medicine, (2013). 2013, 827915.

19. Huang, H, Yang, P, Xue, J, Tang, J, Ding, L, & Ma, Y, et al. Evaluating the Individualized Treatment of Traditional Chinese Medicine: A Pilot Study of N-of-1 Trials. Evidence-Based Complementary and Alternative Medicine, (2014). 2014, 148730.

20. Huang, H, Yang, P, Wang, J, Wu, Y, Zi, S, & Tang, J, et al. Investigation into the Individualized Treatment of Traditional Chinese Medicine through a Series of N-of-1 Trials. Evidence-Based Complementary and Alternative Medicine, (2018). 2018, 5813767.

21. Li, J, Niu, J, Yang, M, Ye, P, Zhai, J, & Yuan, W, et al. Using single-patient (n-of-1) trials to determine effectiveness of traditional Chinese medicine on chemotherapy-induced leukopenia in gastric cancer: a feasibility study. Annals of Translational Medicine, (2019). 7(6), 124.

22. Li, J, Wei, D, Niu, J, Yang, M, Ge, L, & Wang, X, et al. Potential Facilitators and Barriers to Awareness of N-of-1 Trials for Physicians in Traditional Chinese Medicine. Alternative Therapies In Health And Medicine, (2018). 24(2), 44-49.

23. Xie, T, & Yu, Z. N-of-1 Design and Its Applications to Personalized Treatment Studies. Statistics in Biosciences, (2017). 9(2), 662-675.

24. Li, J, Hu, JY, Zhai, JB, Niu, JQ, Kwong, JSW, & Ge, L, et al. CONSORT extension for reporting N-of-1 trials for traditional Chinese medicine (CENT for TCM) : Recommendations, explanation and elaboration. Complementary Therapies in Medicine, (2019). 46, 180-188.

25. Chen, J, Huang, J, Li, JV, Lv, Y, He, Y, & Zheng, Q. The Characteristics of TCM Clinical Trials: A Systematic Review of ClinicalTrials.gov. Evidence-Based Complementary and Alternative Medicine, (2017). 2017, 9461415.

26. Kravitz, RL, Schmid, CH, Marois, M, Wilsey, B, Ward, D, & Hays, RD, et al. Effect of Mobile Device-Supported Single-Patient Multi-crossover Trials on Treatment of Chronic Musculoskeletal Pain: A Randomized Clinical Trial. JAMA Internal Medicine, (2018). 178(10), 1368-1377.

27. Mirza, RD, & Guyatt, GH. A Randomized Clinical Trial of n-of-1 Trials-Tribulations of a Trial. JAMA Internal Medicine, (2018). 178(10), 1378-1379.

28. Kravitz, RL, Sim, I, & Duan, N. A Case for n-of-1 Trials-Reply. JAMA Internal Medicine, (2019). 179(3), 453.

29. Terasawa, K. Evidence-based Reconstruction of Kampo Medicine: Part II-The Concept of Sho. Evidence-Based Complementary and Alternative Medicine, (2004). 1(2), 119-123.

30. Duan, N, Kravitz, RL, & Schmid, CH. Single-patient (n-of-1) trials: a pragmatic clinical decision methodology for patient-centered comparative effectiveness research. Journal of Clinical Epidemiology, (2013). 66(8 Suppl), S21-8.

31. Zucker, DR, Ruthazer, R, & Schmid, CH. Individual (N-of-1) trials can be combined to give population comparative treatment effect estimates: methodologic considerations. Journal of Clinical Epidemiology, (2010). 63(12), 1312-1323.

32. Takahashi, K, Yoshino, T, Maki, Y, Ishiuchi, K, Namiki, T, & Ogawa-Ochiai, K, et al. Identification of glycyrrhizin metabolites in humans and of a potential biomarker of liquorice-induced pseudoaldosteronism: a multi-centre cross-sectional study. Archives of Toxicology, (2019). 93(11), 3111-3119.

33. Sánchez-Vidaña, DI, Rajwani, R, & Wong, MS. The Use of Omic Technologies Applied to Traditional Chinese Medicine Research. Evidence-Based Complementary and Alternative Medicine, (2017). 2017, 6359730.