Study design
The study is a parallel controlled, prospective trial with a two-arm comparative design. Eligible patients will be randomized into the experimental group or control group at a 1:1 ratio, with each group will both have oral Riluzole. The experimental group will conduct PT and Tuina therapy for 4 weeks, while patients in the control group will be instructed to perform basic stretching exercises of the upper and lower limbs at home for 4 weeks. Clinical efficacy and safety measures will be collected at baseline, after 4 weeks, and during follow-ups every 6 months for 2 years. This protocol was approved by the Ethics Committee of Hubei Provincial Hospital of Traditional Chinese Medicine (HBZY2022-C42-01) and will be conducted at Hubei Hospital of Traditional Chinese Medicine. This trial was registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn.) on February 27, 2023, with the identifier ChiCTR2300068650. Figure 1 depicts a simplified flowchart and Table 1 shows the time point of the research. The Protocol Standard Items: SPIRIT is the Recommendations for Interventional Trials [14]. The list is shown in Additional File 1.
Sample size
The sample size is calculated based on the primary outcome ALS Functional Rating Scale-Revised (ALSFRS-R) using PASS15.0 software. According to similar literature[15], the mean for the experimental group is estimated to be 36.0 with a standard deviation of 4.9 and the mean for the control group is 30.6 with a standard error of 6.5. With a power of 80% and an alpha of 5% (two-sided), the minimum sample size per group is 18. Given a drop-out rate of 20%, the minimum sample size in total is 44.
Participants
Patients diagnosed with ALS will be recruited and identified within the screening of Hubei Hospital of Traditional Chinese Medicine from October 2023.
Inclusion criteria
(1) Patients diagnosed with probable, definite ALS, or laboratory-supported probable ALS according to the revised El Escorial criteria [16].
(2) Sporadic or familial ALS.
(3) Mild to moderate disabilities assessed by Sinaki-Mulder stages I-II-III [17].
(4) Forced vital capacity (FVC) must meet or exceed 50% of the anticipated value based on the individual's age, gender, and height.
(5) The residual muscle strength of the limbs reaches or exceeds level 3.
(6) Aged 18 to 80 years, regardless of gender and nation.
(7) Individuals need to be able to comprehend and execute basic motor instructions through verbal communication.
(8) Patients who voluntarily signed an informed consent (IC) form.
Exclusion criteria
(1) Presence of gastrostomy or invasive ventilation (IV).
(2) History of other neurodegenerative diseases.
(3) The prevalence of other neurological conditions, including dementia or cervical spondylitis myelopathy, that resemble ALS or interfere with assessments of its effectiveness.
(4) The presence of any other clinically significant cardiac, pulmonary, hematological, endocrine, or psychiatric disorders.
(5) Pregnant women or women currently breastfeeding.
(6) Within three months before screening, enrollment in other clinical trials.
(7) Individuals with severe or unstable medical conditions are unsuitable for rehabilitation treatment.
Intervention
Patients in both groups will be treated with oral Riluzole of 50 mg twice daily. Patients in the experimental group will conduct PT and Tuina therapy for 4 weeks, which consists of 40 sessions, 5 sessions per week. Patients in the control group will be instructed to perform basic stretching exercises of the upper and lower limbs at home for 4 weeks.
Each session of PT lasts for 30 minutes[20]: (1) Range of Motion (ROM) exercises (10 minutes) obtained through stretching and passive range of motion exercises. (2) Strength training (20 minutes) accomplished through functional exercises based on body weight. Trunk muscle strengthening exercises will be deployed in cases where walking ability is deficient. Engaging in neck strength training is advisable for upper body weakness.
Tuina is performed by a senior therapist after PT. The intensity level of Tuina will be determined based on a physical examination and the therapist's clinical experience, following thorough communication with each patient. The therapist will massage, squeeze, and knead the muscle groups that display signs of atrophy or spasm. Each session will take 60 minutes, with varying durations for specific and nonspecific focus areas.
Follow‑up
After 4 weeks of treatment, each patient will be followed up 4 times every 6 months for a total of 2 years. If the follow-up nurse calls the patient for three consecutive days and cannot be contacted, the patient is considered to be lost to follow-up.
Outcome measurement
The study protocol conducted five assessments for each patient, including baseline (T0), end of 4 weeks treatment, and follow-up points at 6, 12, 18, and 24 months.
Primary outcome
The primary outcome is the change in global function measured by the ALSFRS-R scores[18].
Secondary outcomes
The secondary outcomes of the study include the following:
(1) Disease progression is measured by changes in the ALSFRS-R scale every 6 months.
(2) Limb function is determined by Manual muscle test (MMT), and Modified Ashworth spasm scale (MAS).
(3) Respiratory Function is evaluated by the predicted values of FVC, Vital capacity (VC), Forced expiratory volume in one second (FEV1), FEV1/FVC, Peak expiratory flow (PEF), and Maximal voluntary ventilation (MVV).
(4) Quality of life is measured by 40-item ALS assessment questionnaire (ALSAQ-40) scores.
Statistical analysis
The data analysis will be conducted using SPSS23.0 software. The normality of the measurement data will be assessed using the Kolmogorov-Smirnov test. The mean and standard deviation will represent the measurement data that adhered to a normal distribution. Analysis of variance, t-test of independent samples, and paired t-test are utilized for inter-group and intra-group comparisons. Measurement data that deviate from a normal distribution are represented by the median (with a four-digit spacing) [M (P25 ~ P75)], and the Mann-Whitney U rank sum test is used to compare groups. Counting data are presented as constituent ratio or rate (%). The comparison between groups uses the χ2 tests or the Fisher exact probability method. A pairwise comparison of three groups of classified data is performed to adjust the test level using the Bonferroni method. The observed difference is statistically significant (P < 0.05).
Adverse events
Under the directives established by the International Conference on Harmonization (ICH), a severe adverse event is characterized as an incident that results in mortality, endangers life, mandates hospitalization or prolongs an existing hospital stay, causes prolonged or severe disability, and any significant medical occurrence that has the potential to inflict harm upon the patient or necessitates intervention to avert it. Safety was assessed by physical examination, vital signs, laboratory tests, 12-lead electrocardiogram (ECG), and recording of adverse events (AEs).
Data management
Electronic data capture was used for data entry, verification, storage, and management. The Electronic Case Report Form (eCRF) is prepared following the Ethics Committee-approved case report form. Source documentation, such as scale findings, laboratory test results, and signed IC forms, will be securely preserved in the hospital. The data in the eCRF must match the data in the source papers. All records will be kept in compliance with Good Clinical Practice (GCP) and Chinese legislation.