Evaluation the Efficacy of Acupuncture in Chemotherapy Induced Peripheral Neuropathy
Phase: NA
Conditions: Randomized Controlled Trial, Breast Cancer, Chemotherapy-induced Peripheral Neuropathy, Acupuncture
Sponsor: China Medical University Hospital

NCT03626220 
Version: 5th Edition / Version Date: August 1, 2019                                               
 
 
 
 
Cover Page of Research Project Application 
For 
Evaluation of the Efficacy of acupuncture in Chemotherapy-
induced Peripheral Neuropathy 
 
 
NCT03626220 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCT03626220                                                                                   1 
 
Version: 5th Edition / Version Date: August 1, 2019                                      
2017 Tainan Municipal An-Nan Hospital-China Medical University 
Research Project Application 
A. Basic Information                       Project Number： CMUH106-REC2-117 
Project category 
■Individual 
project        
Principal Investigator of the 
Integrated General Project   
Name of the Integrated 
General Project 
 
 
Project funding 
■Medical research project          Biotechnology research project 
Vendors/Manufacturers commissioned research projects      Others 
Project attributes 
Biology division research project    ■Non-biological division research 
project 
Project nature 
Basic medical research            ■Clinical research   
Animal experiment research       Biotechnology Research     others 
Research experiences of 
applicants 
■Within three years  More than three years  More than five years 
Principle investigator 
Name：Chien-Chen Huang   
Affiliation：Department of Traditional Chinese Medicine, An Nan Hospital, 
China Medical University, Tainan, Taiwan, R.O.C. 
Position：Attending physician      ID card Number：D221242291 
Co-investigators 
Name：Tsung-Jung Ho                  
Affiliation：Department of Chinese Medicine, Hualien Tzu Chi Hospital, No. 707, 
Sec. 3, Chung-Yang Road, Hualien, Taiwan 97002, R.O.C. 
Position：Vice Superintendent      ID card Number：Q121025903 
Name：Tsai-Wang Chang                  
Affiliation：Department of Surgery, An Nan Hospital, China Medical University, 
Tainan, Taiwan, R.O.C. 
Position：Professor               ID card Number：B100964109 
Title of project 
Evaluation of the Efficacy of acupuncture in Chemotherapy-induced Peripheral 
Neuropathy 
Execution period 
From August 1, 2017 to October 10,2020  
 □  Do not submit this project for external review 
 □  Please avoid                                   doctor/professor review of this plan 
Project contact 
Chien-Chen Huang Phone Number +886 912125682 

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Version: 5th Edition / Version Date: August 1, 2019                                      
B. Abstract 
Please summarize the main points of this project within 500 words and customize the keywords 
according to the project's nature. 
Keywords：acupuncture, chemotherapy-induced peripheral neuropathy 
Peripheral neuropathy is currently the second most common side effect after chemotherapy, second 
only to the side effects of blood toxicity. A variety of chemotherapy drugs may induce peripheral 
neurotoxicity and be caused by the cumulative dose of chemotherapy drugs. Symptoms include 
sensory paresthesia, feeling dullness or numbness, glove-like feeling distributed in the palm. The 
currently most effective way is to interrupt the treatment or adjust the dose of chemotherapeutic drugs, 
but it is easy to make patients discontinue chemotherapy. The purpose of this study is to explore the 
impact of acupuncture on neurological symptoms and quality of life. Three kinds of questionnaires 
will be used:(1) Brief pain inventory- short form to assess the extent of pain and the impact of daily 
life. (2) FACT/GOG-NTX-13 (Version 4) assess changes in neurological symptoms; (3) 
WHOQOL-BREF to assess changes in patients' quality of life. The course of treatment was evaluated 
for nine weeks. Changes in neurological function and quality of life will be evaluated before treatment, 
the third week of treatment, the sixth week of treatment, till the ninth week. The aim of this study is to 
confirm that acupuncture can improve peripheral neuropathy after chemotherapy in order to enhance 
breast cancer patients’ quality of life and provide a new opportunity for integrative therapy between 
Chinese and Western medicine.  
 

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Version: 5th Edition / Version Date: August 1, 2019                                      
C. Background and purpose of the research 
Please describe in detail the background, purpose, and importance of this research plan, as well 
as domestic and international research on this plan and important references 
(i) Background of the research 
A variety of neurotoxic chemotherapeutic agents, including platinums (e.g. cisplatin, carboplatin, 
and oxaliplatin), taxanes (e.g. paclitaxel and docetaxel), and vinca alkaloids (e.g. vincristine and 
vinblastine), thalidomide and bortezomib, may induce peripheral neuropathy. Generally speaking, 
sensory nerve dysfunction is more common than motor involvement. It causes hands and feet to feel 
tingling, dullness or numbness symmetrically, a glove-like ("glove-and-stocking type") sensation 
distributed in palms and soles. Patient's touch, vibration, and proprioception senses may be impaired 
under clinical examinations[1].  
CIPN relates to the cumulative doses of chemotherapeutic agents. Sometimes, when chemotherapy 
is stopped, neuropathy symptoms may continue or worsen, which is called a "costing phenomenon." 
Nerve damaging usually starts from the ends of the extremities; while individual doses were 
accumulated, it gradually extends to proximal joints or ganglions. CIPN is currently the second most 
common side, next to hematotoxicity. Within thirty days after chemotherapy, 68.1% of patients may 
develop CIPN, most of which can be relieved or improved, but there are still 30-83% symptoms 
persist over 6 months[1]. 
At present, the most effective way to treat CIPN is to stop the treatment protocol or adjust doses 
of chemotherapy; however, it affects the effect of chemotherapy in degrading tumor growth. Plenty 
of pharmacological or non-pharmacological treatments are still under investigation, such as 
antioxidant medication (e.g. Acetyl-L-carnitine, glutamine, vit B12, fish oil, etc.), anxiolytics (e.g. 
venlafaxine), neuroprotective agents (e.g. infusion of calcium ions, magnesium ions), food 
supplements, acupuncture, light stimulation, etc. Acupuncture with the advantages of clinically 
effective, easy-practice and relatively safe, few studies revealed its effect on CIPN. However, there is 
still a lack of large clinical trials to evaluate its effectiveness[1]. 
(ii) Purpose of the research 
To investigate the efficacy of acupuncture on peripheral neuropathy after chemotherapy 
administration in patients with breast cancer.  
(iii) Importance of the research 
Current studies revealed that acupuncture might be useful on CIPN; however, an insufficient number 
of participants or lack of control groups limit the quality of clinical studies. Therefore, the aim of our 
study to conduct a randomized controlled clinical trial to evaluate the efficacy of acupuncture on 
peripheral neuropathy caused by chemotherapy. 
(iv) Domestic and international researches on this plan 
In 2013, Giovanna Franconi et al. published a systematic review that screened the database of 
MEDLINE, Google Scholar, Cochrane Database, CINHAL, CNKI, Wanfang Med Online, ISI 
Proceedings. The screened year was set before 2012, and 3989 journal articles were screened. With 
excluding acupuncture irrelevant or duplicate articles, or researches unrelated to neuropathy and 

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Version: 5th Edition / Version Date: August 1, 2019                                      
chemotherapy, 98 papers left for quality evaluation, and 7 articles were selected finally which most 
relevant to the effect of acupuncture in treating CIPN. As the results of the two randomized 
controlled-trials selected in the seven articles, a prospective randomized controlled clinical trial 
conducted by Alimi et al. in 2003, auricular acupuncture for 2 months was significant improved in 
visual analog scale(VAS) compared with a controlled group(placebo acupuncture and seeds); 
another randomized controlled trial conducted by Tian et al. in 2011, warm acupuncture and 
moxibustion without knowing treatment duration, the quality of life and neurotoxic symptoms were 
improved compared with neurotropin [2]. 
Raimond et al conducted a phase II clinical trial in 2016, acupuncture-like transcutaneous nerve 
stimulation (ALTENS) was used in the experimental group, and the acupoints were patched on the 
seventh cervical vertebra in combination with Hegu, and the third Lumbar spine in combination with 
Tai-Chong. The protocol included 12 treatments, and 20 minutes remained in each treatment; all 
participants were followed up for 3 and 6 months from the end of treatments. Of 27 patients in 
ALTENS group, 24 completed the 3-month follow-up after treatment, and 23 completed the 6-month 
follow-up. Compared with the real acupuncture group, only 13 people were included. Although the 
results after acupuncture are listed, there were insufficient data to assess the differences between the 
two groups. Although studies have shown that ALTENS relieved symptoms of neurotoxicity using 
Modified total neuropathy score (mTNS), numbness score and Edmonton Symptom Assessment Scale 
(ESAS), there lacked a control group and randomized sampling design in this study[3]. 
Heather Greenlee et al. conducted a pilot study comparing electro-acupuncture(EA) and sham 
electro-acupuncture(EA) to prevent taxane-induced peripheral neuropathy. Yanglingquan, Zusanli, 
Shousanli and Hegu were the main acupoints in the EA group, in addition of acupoints in upper limbs, 
such as Huatuo Jiaji(C5, C7) and Bafeng acupoints, and Huatuo Jiaji(L3, L5) and Baxie in lower 
limbs. Park sham collapsible acupuncture was used to touch the acupoints without penetration in the 
sham electro-acupuncture group. 12 weeks of treatment were designed, and 30 minutes for each 
treatment. The neurological patient-reported outcomes included Brief Pain Inventory-Short Form 
(BPI-SF), Functional Assessment of Cancer Therapy-Taxane (FACT -TAX), FACT-NTX, and 
Neuropathic Pain Scale (NPS) were assessed at week 6, week 12, and week 16. Qualified participants, 
who completed at least 3 weeks of treatment, pre-treatment, and at least one follow-up questionnaire 
in each group, were comparable. However, there were no significant differences between EA group 
and sham EA group in neurological assessments. Further studies should be conducted to evaluate the 
effectiveness of acupuncture in the prevention of CIPN[4]. 
(v) Important references 
1. Susanna B.Park, David Golstein, et al; Chemotherapy-Induced Peripheral Neurotoxicity: A 
critical Analysis. CA CANCER J CLIN. 2013;63:419-437. 
2. Giovanna Franconi, Luigi Manni, et al; A Systematic Review of Experimental and Clinical 
Acupuncture in Chemotherapy- Induced Peripheral Neuropathy. Evidence-Based Complementary 
and Alternative Medicine.2013:p1-7. 
3. Raimond Wong, Pierre Major, et al: Phase 2 Study of Acupuncture-Like Transcutaneous Nerve 

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Stimulation for Chemotherapy-Induced Peripheral Neuropathy. Integrative Cancer Therapies. 
2016; 15(2):153-164. 
4. Heather Greenlee, Katherine D. Crew, et al: Randomized Sham-Controlled Pilot Trial of Weekly 
Electro-acupuncture for the prevention of Taxane-induced Peripheral Neuropathy in Women with 
Early Stage Breast Cancer. Breast Cancer Res Treat. 2016;156:453-464. 
 
 
 
 
 
 
 

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Version: 5th Edition / Version Date: August 1, 2019                                      
D. Research methodology and procedures 
1. Please elaborate on the research methodology and reasons used in this project. 
2. Expected difficulties and solutions 
3. Cooperative use of essential instruments. 
4. For projects that last more than one year, please list them by year. 
(i) Research methodology and reasons 
This randomized controlled clinical trial explores the efficacy of combined acupuncture and drug 
treatment (conventional cancer therapy) in women with breast cancer after chemotherapy causes 
peripheral neuropathy. The study adopted convenience sampling and randomized allocation, all the 
participants were screened from the patients with breast cancer who visited the Department of 
Traditional Chinese Medicine at Tainan Municipal An-Nan Hospital-China Medical University, Tainan. 
Taiwan. 
The inclusion criteria will be: female more than 20 years of age; breast cancer with early-stage at I-
III; had completed chemotherapy; the neurotoxic chemotherapeutic agents included taxanes, platinums, 
or others; less than grade three in the Eastern Cooperative Oncology Group (ECOG) status; higher than 
grade one in National Cancer Institute-common terminology criteria for adverse events(NCI-CTCAE) 
scale. 
The exclusion criteria will be: having less than three months in mean survival time, history of diabetic 
neuropathy before chemotherapy administration, history of other preexisting peripheral neuropathy, 
other inflammatory or metabolic arthritis, severe blood coagulation diseases or with latent bleeding 
tendency, unstable cardiovascular diseases, or other preexisting muscle-skeletal diseases. 
Figure 1 showed the flow chart of the research: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acupuncture 
group(N=25) 
Controlled 
group(N=25) 
Conventional cancer therapy 
Acupuncture 
Sham acupuncture Tx 
1. Basic characteristics of participants 
2. Brief Pain Inventory-short form 
3. FACT/GOG-NTX-13 
4. WHOQOL-BREF 
5. Touch Test Sensory Evaluator 
Screen/selection 
Randomization 
Baseline 
measurement
Entry the 
study 

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treatment(Tx) 
15 Tx within 9 weeks 
15 Tx within 9 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. The flow chart of the study 
The evaluation tools used in the research are: 
(1) Brief Pain Inventory-short form: To assess the location of pain and the level of pain. Items are scored 
from 0 to 10 (0= no pain; 10= pain as bad as you can imagine) to evaluate the degree of pain and the 
impact of pain on daily life. 
(2) FACT/GOG-NTX-13: To evaluate the changes in peripheral neuropathy such as sensory, motor, 
touch, cold and heat sensations, and the impact of pain on daily life. Items are scored from 0–4 (0 = not 
at all; 4 = very much) and summed. 
(3) WHOQOL-BREF (Taiwan version): To evaluate the degree of improvement in the quality of life 
after receiving acupuncture treatment. Items are scored from 1–5 (1 =being very dissatisfied, 2 
=dissatisfied, 3 =No comments, 4 =satisfaction, 5 =very satisfied).  
(4) Touch Test Sensory Evaluator: Use 20 von Frey monofilaments to test the degree of the tactile 
sensation of the patient's fingertips, tips of the toe, palms, and planters. 
The treatment protocol will be designed as: 
(1) The acupuncture group: Acupuncture treatment will be performed for 9 weeks. The frequency of 
acupuncture will be twice a week for the first six weeks, and once a week for the following three 
weeks. 30 minutes needling at each treatment. Acupuncture points include Baihui(GV20), 
Qihai(CV6), Quchi(LI11), Hegu(LI4), Neiguan(P6), or Shenmen(HT7) for upper limbs. For plantar 
numbness, choose two acupoints to use in turn; use Weizhong(BL40), Sanyinjiao(SP6), or 
Zusanli(ST36) for lower limbs. If severe numbness occurred, Taixi(KI3) or Yongquan(K1) should 
be added for feet numbness. “De qi” sensation, such as soreness, numbness, pain, etc. will be 
achieved at each acupoints . 
1. Brief Pain Inventory(short form) 
2. FACT/GOG-NTX-13 
1. Brief Pain Inventory(short form) 
2. FACT/GOG-NTX-13 
1. 
Brief Pain Inventory(short form) 
2. 
FACT-NTX 
3. 
WHOQOL-BREF 
4. 
Touch Test Sensory Evaluator 
At week 3 
(6 treatments) 
At week 6 
(12 treatments) 
End of study 
At week 9 
(15 treatments) 
Follow-up for 
3weeks 

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Version: 5th Edition / Version Date: August 1, 2019                                      
(2) The controlled group: Acupuncture with minimal needling 0.5 cun (estimated 1cm with deviation 
depends on the body size of each participant) away from the acupoints, which only superficially 
penetrated the skin without the feeling of “De Qi” sensation. 
The conventional cancer treatment for CIPN was the same in the two groups. 
Within nine weeks of treatments, questionnaires were assessed before treatment, at week three, week 
six, and week nine to follow-up the changes of peripheral neuropathy on each participant. 
Explore the neuroprotective mechanism of acupuncture: 15 cc of blood samples will be drawn before 
and after 15 sessions of treatments from participants in both groups. The blood samples will be analyzed 
by enzyme-linked immunosorbent assay (ELISA) for tumor necrosis factor-alfa and interleukin- 6, 
interleukin-10 and brain-derived nuerotrophic factor to evaluate the differences in the inflammation state 
of the peripheral nervous system within and between groups. 
Statistical analysis: 
This is a two-group, parallel controlled clinical trial; the null hypothesis will be no significant difference 
in BPI-SF between the two groups. The estimated standard deviation was 2, the power was set to 94%, 
a two-tail test, α=0.05, and the estimated number of patients was at least 25 in each group. 
A two-sample t-test will be used to compare the difference between the treatment group and the 
controlled group. 
A Paired-t-test will be used to compare the changes in the assessment scale at week 3, week 6 and week 
12. 
One way ANOVA: Analyze the relationship between the demographic data of subjects, breast cancer 
grade and other category variables and the evaluation scale. 
(ii) Expected difficulties and solutions 
The treatment group often withdrew from the trial due to frequently acupuncture or bleeding caused by 
acupuncture. The solution is to specify the possible side effects of acupuncture, such as bleeding or 
bruising, in the informed consent form. 
The control group may not be able to continue treatment due to low efficacy. The way of solution is to 
strive for subject allowances.  
                                                        

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Version: 5th Edition / Version Date: August 1, 2019                                      
E. The expected work items and specific results 
1. Please list the work items expected to be completed within the implementation period. 
2. Expected contributions to academic research, national development and other applications. 
3. Expected training for participating staff members. 
4. For projects that last more than one year, please list them by year. 
(i) Work items expected to be completed within the implementation period 
1. To submit the protocol to the Research Ethics Committee of the hospital for ethical review.  
2. To establish patients’ basic characteristic datasheets. 
3. To obtain authorization and preparation of assessment scales 
4. To update related articles in journals or books about the study 
5. To pre-test and adjust study procedures. 
6. To screen eligible participants and complete the assessments  
7. documentation of study data.  
8. statistical analysis. 
9. Prepare an interim report 
10. Prepare results reports  
11. Send an application for the research funding. 
 
(ii) Expected contributions 
Until now, most studies focused on the effect of acupuncture or traditional Chinese formulas 
in the treatment of CIPN. The aim of this study is to investigate the effect of acupuncture with 
conventional cancer therapy in the treatment of CIPN, in order to prove the effect of intervention 
with traditional Chinese medicine in treating cancer treatment-related symptoms. 
 
(iii) Expected training for participating staff members 
The staff participating in the research will understand the research ethics, the process of 
experimental design, the importance of the informed consent form, and the authorization and 
preparation of evaluation tools. Through data collection and analysis, the staff can learn how to 
use statistical software, data analysis, and write credible professional medical articles.