Study design
This study will be a multicentre, three-arm (including AA group, SAA group, and WL group), single-blind, prospective randomized controlled trial, approved by the Ethics Committee of Hospital of Chengdu University of Traditional Chinese Medicine (2021KL-015), and jointly funded. No less than 360 participants for one type of NCV will be advertised and enrolled and randomly assigned to one of the three groups. To examine the effective of AA therapy in preventing and (or) relieving AEFI related to NCV, measurements will be taken once the injection is completed, and the participants will be followed after 1, 3, 5, 7, and 14 days after NCV injection. Participants will be asked to accept assessments at baseline. This randomized controlled clinical trial began recruitment on March 17th, 2021 and the anticipated completion date is February 2022. The primary outcome are quality and quantity evaluation among participants who reported any AEFI and who reported local pain at injection site. The flow chart of the trial is shown in Figure 1, and the participant timeline is listed in Table 1. Informed consent is obtained from each participant. The protocol is reported following the SPIRIT guidelines [30].
Table 1: The participant timeline of our study
Timepoints
|
Recruitment
|
Allocation
|
The first dose
|
-T1
|
0
|
T1*
|
T2*
|
T3*
|
T4*
|
T5*
|
Entry items
|
Inclusion / Exclusion
|
X
|
|
|
|
|
|
|
Informed consent
|
X
|
|
|
|
|
|
|
Randomization
|
|
X
|
|
|
|
|
|
Precautions for distribution
|
|
|
X
|
|
|
|
|
Interventions
|
Auricular point acupressure
|
|
|
![](https://myfiles.space/user_files/58894_9946feeafa4c1df7/58894_custom_files/img1635478448.JPG)
|
|
|
Sham auricular point acupressure
|
|
|
![](https://myfiles.space/user_files/58894_9946feeafa4c1df7/58894_custom_files/img1635478459.JPG)
|
|
|
Wait-list control
|
|
|
Wait-list control
|
Follow-ups
|
Baseline characteristics
|
|
X
|
|
|
|
|
|
Local pain at injection site#
|
|
|
X
|
X
|
X
|
X
|
X
|
Headache#
|
|
|
X
|
X
|
X
|
X
|
X
|
Muscle and (or) joint pain#
|
|
|
X
|
X
|
X
|
X
|
X
|
Fatigue#
|
|
|
X
|
X
|
X
|
X
|
X
|
Nausea#
|
|
|
X
|
X
|
X
|
X
|
X
|
Vomiting#
|
|
|
X
|
X
|
X
|
X
|
X
|
Diarrhoea#
|
|
|
X
|
X
|
X
|
X
|
X
|
Other AEFI reported by participants but not listed above#
|
|
|
X
|
X
|
X
|
X
|
X
|
Adverse events of the interventions*
|
|
|
X
|
X
|
X
|
X
|
X
|
Note: T1 *: Immediately after the first or second dose of vaccine; T2 *: 3 days after the first or second dose of the vaccine; T3 *: 5 days after the first or second dose of vaccine; T4 *: 7 days after the first or second dose of vaccine; T5 *: 14 days after the first or second dose of vaccine; #: Record as cases with visual analog scale (VAS) scores from 0 to 10; Adverse events of the interventions *: including abnormal pain, skin allergy and other adverse reactions.
Inclusion criteria
Vaccinators will be screened strictly for meeting the criteria of the NCV injection shortly before the injection (during registration) [31]. Patients will be included if they meet all the following criteria:
1) Conforming to the conditions of the injection without contraindication, and completing the NCV injection within 24 hours before screening;
2) No headache, muscle or joint pain, fatigue, diarrhoea, nausea or vomiting experienced (no more than 4 scores, VAS) within three days before the injection, and no diseases (diagnosed) presenting the symptoms above;
3) No redness, swelling, injury or infection on the skin or soft tissue of bilateral ears;
4) No history of alcohol and adhesive tape contact allergy;
5) Able to complete the follow-up questionnaires independently online or by phone;
6) Agree to participate and sign the informed consent, and abide by precautions after the injection and requirements of AA therapy.
In addition, it should be pointed out that due to the emergency of NCV injection and the good safety of AA therapy, we do not restrict ages and genders among participants. We will conduct sub-groups for different ages for comparison.
Exclusion criteria
Patients will be excluded if they have one or more of the following:
1) Not suitable to be vaccinated because of contraindication or were in cautious condition;
2) Have participated in other trials within 4 weeks before the start of this study;
3) With headache, muscle or joint pain, fatigue, diarrhoea, nausea or vomiting experienced (serious than 4 scores, VAS) within three days before the injection, or with diseases (diagnosed) presenting the symptoms above;
4) Pregnant or lactating women;
5) With other serious primary diseases and psychosis.
Withdraw from the trial
Participants will be allowed or asked to drop out from the trial if they:
1) Are lost to follow-up
2) Become pregnant
3) Develop serious adverse event (SAE)
Participants can withdraw from this clinical trial at any time. The date and reason for withdrawal should be stated. If possible, all subjects withdrawing from the study should continue to be followed up regularly on a measurement schedule with a final assessment for intention-to-treat analysis.
Recruitment
We will recruit participants through leaflets and posters when waiting for the injection, and will be advertised, recruited during remaining in the medical institutions for post-injection observation (at less 30 mins). Trial investigators will examine respondents in the observation areas for eligibility screening. Informed consent will be obtained from eligible patients before randomization.
Intervention
All researchers received enough pre-experiment training, and acupuncturists who performed AA and SAA were trained for at least 4 years with clinical experience. Five auricular acupoints were applied for both AA and SAA groups, bilaterally, including Shenmen (TF4), Pi (Spleen, CO13), Xin (Heart, CO15), Pizhixia (Subcortex, AT4), Jiaogan (sympathetic, AH6a) for AA group, and Gangmen (Anus, HX5), Niaodao (Urethra, HX3), Helix 1 (HX9), Helix 2 (HX10), Helix 3 (HX11) for SAA group (Figure 2 and Table 2).
Table 2: Auricular acupoints selected in our protocol (with location and function)
Group
|
Auricular acupoints
|
Anatomical location
|
Main function(s) according to TCM
|
For the auricular acupressure group
|
Shenmen (TF4)
|
The upper part of the posterior 1 / 3 of the triangular fossa of auricle (Area 4 of auricle triangular fossa)
|
Insomnia, abnormal sweating, pain, cough, asthma, vertigo, hypertension, allergy, Withdrawal Syndrome, epilepsy
|
Pi (Spleen, CO13)
|
Below the BD line of the auricle and above the posterior part of the concha cavity (Concha 13 area of auricle)
|
Diarrhea, abdominal distention, constipation, loss of appetite, functional uterine bleeding, excessive leucorrhea, inner ear vertigo, edema, visceral ptosis
|
Xin (Heart, CO15)
|
In the middle of the concha cavity of the auricle (Concha 15 area of auricle)
|
Tachycardia, arrhythmia, angina pectoris, spontaneous sweating, night sweats, hysteria, sore tongue, palpitation, insomnia, forgetfulness
|
Pizhixia (Subcortex, AT4)
|
On the inner side of the opposite tragus of the auricle (Zone 4 of the opposite tragus of the auricle)
|
Pain, neurasthenia, gastric ulcer, pseudomyopia, diarrhea, hypertension, coronary heart disease, arrhythmia, insomnia
|
Jiaogan (sympathetic, AH6a)
|
At the junction of the anterior segment of the lower foot of the opposite ear wheel of the auricle and the inner edge of the ear wheel (Anterior segment of zone 6 of the opposite ear wheel)
|
Autonomic nervous function diseases, visceral pain
|
For the sham auricular acupressure group
|
Gangmen (Anus, HX5)
|
In front of the triangular fossa of the auricle (Ear wheel area 5 of the auricle)
|
Hemorrhoids, anal fissure
|
Niaodao (Urethra, HX3)
|
At the anterior and upper part of the protrusion of the foot of the auricle (Ear wheel area 3 of the auricle)
|
Frequent urination, urgent urination, urinary pain, urinary retention
|
Helix 1 (HX9)
|
Below the tubercle of the auricle (Ear wheel area 9 of the auricle)
|
Tonsillitis, upper respiratory tract infection, fever
|
Helix 2 (HX10)
|
Just below the Helix 1/ HX9 (Ear wheel area 10 of the auricle)
|
Helix 3 (HX11)
|
Just below the Helix 2/ HX10 (Ear wheel area 11 of the auricle)
|
Auricular acupoints for AA group and SAA group were selected according to relevant international and national standards of China, expert consultation, our experience, and based on potential AEFI of the vaccines from previous studies [4-6,16-19,32-34]. Tools (model “Ziyu”; He’s Medical Device Co., Ltd, Henshui, China) applied for AA and SAA were Semen Vaccariae (about 2 mm in diameter), which were black, round, hard and very small without special smell, covered with small tapes (about 0.8x0.8 mm2) (Figure 3).
Surface of the auricular acupoints, marked on stick figures with two protocols associated with the sequence numbers for AA and SAA, was cleaned and dried with disinfection swabs, and Semen Vaccariae tapes were pasted in the acupoints by the acupuncturists and pressed with fingers to achieve sensation of soreness or distention.
In addition, the participants in AA and SAA groups were informed to press the tapes by themselves for 1 minute vertically and appropriately to achieve the sensation, with a duration of 4 to 5 times a day and 5 days in total. The content above was written in Attention After AA Therapy, which were distributed to the participants with the individual sequence number recorded.
All of these were free for the participants, and they were informed at the beginning of the trial that two sessions of AA therapy, based on individual health condition, would be provided for free upon accomplishment of the study.
Outcomes
All outcomes will be accessed and evaluated from the participants online or by phone in 1, 3, 5, 7, and 14 days after NCV injection, which they thought might be related to the injection. Primary outcomes are percentages of participants who reported any AEFI and who reported local pain at injection site, with their severity evaluated by visual analog scale (VAS) scores of 0–10. Secondary outcomes include percentages of participants who reported headache, muscle and (or) joint pain, fatigue, nausea, vomiting and diarrhoea, together with other AEFI reported by participants but not listed above, and with their severity evaluated by the VAS scores, similarly. In addition, AEFI with extra specific medical intervention will be recorded. Adverse events associate with the AA therapy for AA and SAA groups will also be recorded, with cases, severity, measurement and outcomes. Follow-ups will be performed by blinded evaluators.
Due to the large number of vaccinations in facilities, especially in the waiting and observation areas, time-consuming questionnaires and indicators with more complexity will not be implemented.
Assignment and blinding
After confirmation for eligibility and collection of written informed consents, participants will be randomized through a random allocation software (The Hefei Big Orange Software Technology Co., Ltd, V 2.1.8), and be allocated to the AA, SAA, and WL groups in a 1:1:1 ratio with stratifying by centres. Sequentially numbered sequences with combination of numbers and letters will be performed and recorded by registrars to conceal the random sequence for the participants, outcome assessors and statisticians. The sequences will be generated and concealed by trained research assistants. The participants in the AA group and SAA group, and outcome assessors, statisticians will be blinded, while participants in the WL group and the acupuncturists will not.
Sample size calculation
No less than 360 participants will be randomized in 1:1:1 ratio to each group. This is a protocol for an explorative study, therefore, a formal sample size is unavailable and not calculated.
Statistical analysis
Clinical outcomes will be analysed in both intention-to-treat (ITT) and per-protocol (PP) participants, and missing values will be imputed by the last-observation-carried forward method. Results of participants who received AA, SAA or WL observation, and with baseline details recorded will be processed with ITT analyses, while those who complete all the 14-day evaluation and with the interventions applied correctly will be analysed with PP sets.
Descriptive analyses will be made of frequencies and percentages for the qualitative variables, and overall p values will be estimated by χ2 or fisher χ2 test as appropriate with the Bonferroni approach. Pairwise comparisons will be performed as differences of percentages (DP), with 95% CIs of the differences calculated by R (V4.0.1). Estimations for p values of the pairwise comparisons will be performed by χ2, continuous or fisher χ2 test as appropriate in SPSS (V23.0). Two-tailed tests with p < 0.05 define statistically significant for all analyses.