Background

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by typical repetitive behaviors and communication difficulties [1]. It has a childhood onset, and patients with this condition have lifelong difficulties with social interaction, communication, and sensory perception [2]. The etiology of ASD involves complex and polygenic interactions as well as possible environmental factors [3]. ASD is a serious public health problem worldwide, with its high morbidity and disability rates garnering increasing attention. Based on the epidemiological studies, the incidence rate of ASD is > 1–2% [4].

However, there are no specific agents for the treatment of ASD, which is currently treated with behavioral interventions such as early parent-mediated interventions [5,6,7,8]; naturalistic behavioral developmental interventions; behavioral and social treatments for school-age children, adolescents, and adults [9,10,11,12]; and even medical clown interventions [13]. These clinical interventions can significantly improve the social adaptability of children with ASD.

Clinical treatment of ASD using evidence-based pharmacology is limited to treating the co-occurring behavioral problems caused by mental illness rather than ASD itself. Risperidone [14,15,16,17] and aripiprazole [14, 18, 19] have been approved by the Food and Drug Administration to improve irritability or restlessness in children and adolescents with ASD. However, both drugs can cause adverse effects, including sedation and weight gain after long-term use, which increases the risk of subsequent health problems [19].

To alleviate the clinical symptoms of ASD and to save medical costs, traditional therapies have been used in the treatment of ASD with numerous advantages.

Tuina is an important and effective external treatment in improving stunting [20] and decreasing physical and mental tension [21], among other benefits. Currently, some Tuina manipulations have been applied as interventions for children with ASD [22, 23] with a certain degree of success [24]. Qigong Tuina, which is a specific Tuina intervention in children with ASD [25, 26], has been shown to improve the symptoms of children with ASD.

Pediatric Tuina is a traditional Chinese medicine (TCM) therapy that acts on specific acupoints on the hands, back, and arms [27], including Wu**g acupoints for different fingers. These acupoints target the spleen, liver, heart, lung, and kidney based on the meridian and collateral theory. The order is located on the thread surface of the five fingers in children (the spleen acupoint is located on the thumb). Stimulating different acupoints by specific manipulations has various curative effects.

However, there is no strong evidence regarding the single-use of pediatric Tuina intervention for ASD treatment [28]. The two objectives of this study are (1) to further evaluate the effectiveness of pediatric Tuina as a complementary therapy for children with ASD aged 2–6 years, by comparing it with conventional treatment through a standardized clinical study design, and (2) to promote and facilitate the use of pediatric Tuina in ASD by allowing more children with ASD to benefit from Tuina as a healthy and environmentally friendly physical therapy.

Methods/design

Study design

This will be a randomized controlled trial. To meet ethical requirements and considering the particularity of ASD, this study will not employ a blind design. The trial will be conducted at Hunan University of Chinese Medicine, China, from November 2020 to December 2022. Eligible children will be randomly divided into the pediatric Tuina plus conventional treatment group or the conventional treatment group based on a computer-generated random table at a ratio of 1:1. Efficacy will be assessed using the Childhood Autism Rating Scale (CARS) and the Autism Treatment Evaluation Checklist (ATEC). Before study commencement, all participants will be assessed using a scale by a third party not involved in the study. The baseline level of the participants will be determined at the time of enrollment; further, the participants will be evaluated again after the 30th treatment, with a follow-up period of 6 months postoperatively. Figure 1 shows the flowchart of the study.

Fig. 1
figure 1

Flowchart of the study. A total of 400 participants will be randomized to the two groups. The interventions will last for 25 min and will be conducted two times per week for 6 weeks, and a 6-month follow-up was performed after treatment. The main efficacy score will be based on the CARS, and the secondary outcome indicators will be evaluated using the ATEC. CARS, Childhood Autism Rating Scale; ATEC, Autism Treatment Evaluation Checklist

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Participants

This study will recruit 400 children with ASD from autism organizations certified by the Hunan Disabled Persons' Federation, including **ngxueyuan Education Development Center (Tianxin District, Changsha City), Aimeng Rehabilitation Center for Special Children (Yuhua District), and Vitality Autism Rehabilitation Center (Yuelu District), among others.

Eligibility criteria

Inclusion criteria

1. Diagnosis made by a psychiatrist based on the diagnostic criteria for ASD of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)

2. Age: 2–6 years old

3. CARS score ≥ 30 points

4. The guardian of the child is informed of the study and the child is compliant with the treatment cycles

5. No history of participation in other observational studies or unplanned interventions within the past 30 days, such as acupuncture and herbal treatment that may affect the study results

6. No history of other serious diseases that may affect the outcomes, including organic pathologies, coagulation disorders, congenital heart disease, and epilepsy

7. No history of chronic or acute infections, such as pneumonia

8. No history of other psychiatric disorders, such as ADHD

Exclusion criteria

1.Children who are resistant to the Tuina intervention, with persistent crying and inability to adapt

Children who during the study develop conditions like phlebitis, open wounds, and skin breakdown in the manipulated area

Elimination criteria

1. Children who do not complete 30 intervention sessions following the research protocol

2. Children who received other interventions that may affect the study results

Drop-out criteria

1. Children experiencing adverse events during the trial, such as pneumonia and skin disease, and who could not adhere to the Tuina therapy.

2. Children whose guardian perceived the treatment as ineffective and therefore terminated the treatment.

3. Children withdrawing from the treatment at the original rehabilitation institution or after being transferred to a different rehabilitation institution.

Interventions

Control group

Based on the training of the autism organization mentioned above in this protocol, the control group will strictly follow the five schedule sessions of applied behavior analysis training, five key skill training sessions, five music group training sessions, five oral muscle training sessions, and five sensory training sessions per week. Only teachers with a background in special education will participate in the study.

Tuina group

The Tuina group will receive a total of 30 sessions of pediatric Tuina (five sessions per week for 6 weeks, and a follow-up session at the 12th week after the end of treatment). From the perspective of humanistic care, to make the child feel safe, the child will be held by the parents or relatives during the session and placed in a sitting position. Tuina will be performed face to face. When performing acupoint Tuina on the back, the child will lie on his parents or relatives in a prone position.

To standardize the Tuina manipulation, only certified Chinese medicine physicians with 3 months of training in Tuina techniques will perform the procedures. The acupoint prescriptions are mainly based on the TCM theory of the relationship between Du Meridian and the Brain. After gathering clinical evidence and soliciting the opinions of experienced Tuina experts, we have summarized the following acupoints and manipulation times of Tuina. Table 1 presents the detailed information.

Table 1 Tuina acupoints, manipulation times, and methods
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Outcome assessment

The results will be evaluated by a third party otherwise uninvolved in the study. This study will be conducted at the Mental Health Center of the Second **angya Hospital of Central South University, Hunan Province, China.

Primary outcomes

The main efficacy score will be based on the CARS, which covers interpersonal relationships, imitation, and other 15 aspects, with a total score of 60 points. Each aspect will be scored using a four-point scale: age-appropriate (score 0), mildly abnormal (score 1), moderately abnormal (score 2), and severely abnormal (score 3). Participants with a score < 30, 30–35, and ≥ 36 are considered as non-autistic, moderately autistic, and severely autistic, respectively. Outcomes will be evaluated after the 30th treatment session. Follow-up efficacy assessment will be performed at 6 months post-treatment. The difference in CARS before and after the intervention will be considered significant, effective, and ineffective if the reduction is greater than 10, 5–10 (inclusive), or less than 5 points, respectively [29]..

Secondary outcomes

The secondary outcome indicators will be evaluated using the ATEC, which includes four aspects: (1) speech/language/communication, (2) sociability, (3) sensory/cognitive awareness, and (4) health/physical/behavior [30]. With a total of 77 items, each item is rated using a 3-point scale (never, sometimes, and always; recorded as 0, 1, and 2 points, respectively) or a 4-point scale (none, mild, moderate, and severe; recorded as 0, 1, 2, and 3 points respectively). The main purpose of this study is to clarify the improvement in children with ASD after Tuina therapy from different perspectives. The evaluation time points for this outcome are consistent with those of the primary outcomes.

Safety assessment

Although pediatric Tuina is a nature-based approach to healing without side effects, some adverse events (AEs) may occur during the treatment process due to medical errors. Skin damage is the most common AE during Tuina. To prevent AE occurrence, strict monitoring will be conducted. In the case of AEs, the researchers will record the time and severity of the AE and promptly deal with it.

Participant timeline

We have designed the schedule for the recruitment, intervention, evaluation, and follow-up of the participants, as shown in Fig. 2.

Fig. 2
figure 2

Study schedule for recruitment, interventions, outcome measurements

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Sample size estimation

The sample size calculation for this study should use a superiority test with two independent sample means to test the scientific hypothesis that both Tuina and conventional treatment are effective for treating children with ASD, but the efficacy of the Tuina treatment may be superior. According to the primary outcome, a difference of more than 5 in the CARS from before to after the intervention is considered to indicate effectiveness [29]. In our initial clinical study [Data collection and management

All parents of children with ASD participating in the project will sign the informed consent form and complete the case report form. Finally, a data file will be established and will be kept and collected by a dedicated person from the Data Committee of the First Affiliated Hospital of the Hunan University of Chinese Medicine. It is important to emphasize that data custodians must maintain their independence and access and audit the data on a regular or irregular basis, thus ensuring that no one can tamper with the data. Inspectors will regularly check the informed consent form, research protocol, and evaluation scale to ensure the quality of the clinical research. Regarding the authenticity of the study, all involved researchers will be blinded to the data. Based on the data disclosure requirements of the CHICTR, the data of this study will be uploaded to the Baidu Cloud Disk or the website of the School of Acupuncture-Moxibustion and Tuina of Hunan University of Chinese Medicine (zjtn.hnucm.edu.cn) within 6 months after the study completion and will be made publicly available. The premise is that the main research results will be published. All nonmembers should sign an agreement form before accessing the research results.

Statistical analyses

All data will be analyzed using SPSS (version 21.0; IBM Corp., Armonk, NY, USA); further, all analyses will be conducted using a two-sided test. Normally and non-normally distributed measurement data will be analyzed using the t-test and rank-sum test, respectively. The significance level will be set at 5% [32].

Ethics

To protect the legitimate rights and interests of all our project participants, we will apply for a clinical research ethics review. This study has been approved by the Ethics Committee of the First Affiliated Hospital of Hunan University of Chinese Medicine (HN-LL-KY-2020-020-01).

Protocol amendments

Any significant protocol revisions will be submitted to the Ethics Committee of the First Affiliated Hospital of Hunan University of Chinese Medicine for approval. After obtaining approval, the changes will be updated on CHICTR.

Ancillary and post-trial care

Tuina is a safe and effective intervention with low probability of AEs, but accidents might occur during the study. If a child with ASD encounters an adverse event during the trial, we will report it to the ethics committee of the First Affiliated Hospital of Hunan University of Chinese Medicine, and a committee of medical experts will determine whether the adverse event is related to the trial. We will also provide treatment costs and financial compensation for study-related injuries based on the actual situation.

Dissemination policy

The results of this study will be disseminated in multiple formats after statistical analysis. They will be published in advanced peer-reviewed journals related to ASD, TCM, or complementary alternative medicine research, or in the form of scholarly reports.

Discussion

ASD development is irreversible, with some symptoms persisting throughout life. Given that improving the quality of life of children with ASD is the common pursuit of all treatments, we should actively explore traditional and non-traditional alternatives to identify the most suitable treatment for ASD.

TCM contains profound wisdom from Chinese philosophy and medical knowledge. Consistent with modern medicine, TCM considers the brain to control emotions, consciousness, and thinking. However, in this theory, the brain is not just the organ in charge of those capabilities, as it has several other functions. The cause of autism is related to the brain; this is a consensus in academic circles. Specific acupoints can improve brain function and promote nerve development. Du Meridian is a special meridian closely associated with the physical location and function of the brain [

Study limitations

First, the diagnosis of ASD will not be made using the Autism Diagnostic Interview-Revised or Autism Diagnostic Observation Scale due to copyright restrictions; instead, the DSM-5 will be used.

Regarding the evaluation, there are no objective biomarkers for evaluating the efficacy of ASD treatments. This study will employ a scale to evaluate the efficacy of the ASD treatment, which may lead to subjective errors.

Additionally, it is impossible to blindly perform Tuina therapy. Furthermore, the standardization of Tuina techniques and stimulation amount varies from person to person. There will inevitably be some differences in specific operations. To reduce such errors, only Tuina therapists with rigorous training and professional qualifications will participate in the study to ensure standard treatment.

Finally, given the ethical requirements, it is not possible to prohibit all children from participating in other educational or behavioral interventions. Therefore, a single Tuina intervention trial is insufficient to evaluate its feasibility for clinical application.

Trial status

The recruitment of patients for this clinical trial, which started in November 2020 and ended in September 2021, it is now entering the clinical intervention phase. The trial was registered in the Chinese Clinical Trial Registry on 28 November 2020 (registration number: ChiCTR2000040452).