Study setting {9}
This study is 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. Participants will be advertised and enrolled in four centres in Chengdu, China, including Hospital of Chengdu university of Traditional Chinese Medicine, Caotang Community Health Service Center, Xi’an Road Community Health Service Center, and Wenjiang School Hospital of Chengdu University of Traditional Chinese Medicine. To examine the effectiveness 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 17, 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 Fig. 1. Informed consent is obtained from each participant. The protocol is reported following the Trials structured template [30].
Eligibility criteria {10}
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:
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1)
Conforming to the conditions of the injection without contraindication, and completing the NCV injection within 24 h before screening
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2)
No headache, muscle or joint pain, fatigue, diarrhoea, nausea, or vomiting experienced (no more than 4 scores, VAS) within 3 days before the injection, and no diseases (diagnosed) presenting the symptoms above
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3)
No redness, swelling, injury, or infection on the skin or soft tissue of bilateral ears
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4)
No history of alcohol and adhesive tape contact allergy
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5)
Able to complete the follow-up questionnaires independently online or by phone
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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:
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1)
Not suitable to be vaccinated because of contraindication or were in cautious condition
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2)
Have participated in other trials within 4 weeks before the start of this study
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3)
With headache, muscle or joint pain, fatigue, diarrhoea, nausea, or vomiting experienced (serious than 4 scores, VAS) within 3 days before the injection, or with diseases (diagnosed) presenting the symptoms above
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4)
Pregnant or lactating women
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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:
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1)
Are lost to follow-up
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2)
Become pregnant
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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.
Who will take informed consent? {26a}
Paper informed consent will be obtained from eligible patients by pre-appointed researchers (C. W., Z. X., H. L. and C. S.) during enrolment but before randomization.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
No biological sample will be collected in our study.
Interventions
Explanation for the choice of comparators {6b}
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 NCVs from previous studies [4,5,6, 16,17,18,19, 32,33,34].
Intervention description {11a}
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), and Jiaogan (sympathetic, AH6a) for AA group, and Gangmen (Anus, HX5), Niaodao (Urethra, HX3), Helix 1 (HX9), Helix 2 (HX10), and Helix 3 (HX11) for SAA group (Fig. 2 and Table 1).
Table 1 Auricular acupoints selected in our protocol (with location and function) 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 0.8 × 0.8 mm2) (Fig. 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 min 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.
Criteria for discontinuing or modifying allocated interventions {11b}
Participants will be allowed or asked to discontinue the trial if they meet any item of the withdraw criteria. In addition, due to the pandemic, they can discontinue the trial at any time with the date and reason recorded.
Strategies to improve adherence to interventions {11c}
All of the AA and SAA interventions and service will be 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.
Relevant concomitant care permitted or prohibited during the trial {11d}
Implementing AA or SAA therapies for the AEFI will not require alteration to usual care pathways (including use of any medication) and these will continue for both trial arms.
Provisions for post-trial care {30}
Not applicable because AA therapy is non-invasive and non-pharmaceutical, easily taught and self-implemented, inexpensive, and with nearly no side effect.
Outcomes {12}
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 analogue 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.
Participant timeline {13}
The participant timeline is listed in Table 2.
Table 2 The participant timeline of our study Sample size {14}
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.
Recruitment {15}
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 min). Trial investigators will examine respondents in the observation areas for eligibility screening.