Study setting {9}
Potential participants with cerebrovascular disease with a history of aspiration pneumonia will be recruited from the National Hospital Organization Yonezawa Hospital, Minamisanriu Hospital, Kesennuma City Motoyoshi Hospital, Saka General Hospital, Sendai Tomizawa Hospital, and Ikeno Clinic.
When a patient matches the eligibility criteria, the physician will contact the administrator.
If the participants are interested in our study, they will be informed about the purpose and content of research as well as the benefits and drawbacks of participation in detail.
After screening, the participants meeting the inclusion criteria will be enrolled.
The study flow is shown in the SPIRIT Figure (Fig. 1).
Participants will undergo treatment for a period of 12-month.
Eligibility criteria {10}
Inclusion criteria
All eligible participants should meet the following criteria:
(1) Patients with cerebrovascular disease with a history of aspiration pneumonia
(2) Patients in the lifetime (maintenance stage or chronic stage) of rehabilitation for cerebrovascular disease
(3) Patients in, out of, or receiving home care at a joint research facility
Exclusion criteria
Participants with any one of the following will be excluded:
(1) Patients with serious diseases, such as chronic respiratory diseases, malignancies, and chronic ischemic diseases, that can result in pneumonia
(2) Patients with metal allergies
(3) Patients with severe skin disorders
(4) Patients who do not develop a swallowing reflex at the time of the initial latent time of swallowing reflex (LTSR) measurement.
(5) Patients with three or more severe aspiration pneumonia episodes in the past three months.
Who will take informed consent? {26a}
The study administrator or a physician at the collaborating hospital will explain the procedure to the patient or family and obtain their informed consent.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable.
Interventions
Explanation for the choice of comparators {6b}
The aim of this study is to investigate the protective efficacy of press needle stimulation for aspiration pneumonia in patients with cerebrovascular disorder.
Press needle stimulation has been found to significantly improve swallowing function in patients with cerebrovascular disorder compared to placebo press needle stimulation [11]. Therefore, a placebo press needle was chosen as placebo control in our trial.
Intervention description {11a}
Participants will receive press needle stimulation at two acupuncture points ST36 (Zusanli) and KI3 (Taixi) [14] on the lower limbs for 12-month. According to traditional Chinese medicine, stimulation of these two acupuncture points is beneficial in the age-related decline in swallowing function. Press needle is a therapeutic device in which an acupuncture needle is safely secured to a circular surgical tape. Pionex Zero (Seirin Corporation, Shizuoka, Japan) non-invasive press needles will be used in this study (Fig. 2). The irritation area in contact with the skin is not a needle but a protrusion, which is designed not to penetrate the skin. While the previous study used an invasive device [11], the present study used a safer one, taking into account the observation period of 12-month. The safety and quality of Pionex Zero are controlled by the Japanese Ministry of Health, Labour and Welfare (Notification Number: 22B1X00006000004). As the sham press needle used for the control group, the protruding part of the Pionex Zero is removed. The authenticity of this Sham device has been confirmed [15]. The press needles and sham press needles will be replaced twice a week in the intervention group and control group, respectively.
Criteria for discontinuing or modifying allocated interventions {11b}
In cases of skin abnormality in the area of application of the press needles, physicians will be consulted and the intervention paused for a period of time. Subsequently, physicians will be consulted about the possibility of resuming treatment. The intervention will also be discontinued if other diseases develop during the period and require treatment.
Strategies to improve adherence to interventions {11c}
Frequent bedside visits and health assessments will be an important part of monitoring adherence.
Relevant concomitant care permitted or prohibited during the trial {11d}
Usual treatments for cerebrovascular disease, its sequelae, and aspiration pneumonia are acceptable. High-dose steroids and immunosuppressive therapy are unacceptable.
Provisions for post-trial care {30}
Treatment with press needle shall be allowed to continue after the observation period depending on the participant’s will. This will also apply to participants assigned to the control group. The costs will be borne by the participant.
Outcomes {12}
Primary outcome
The primary outcomes will help determine whether aspiration pneumonia is prevented and if press needle stimulation is effective. The primary outcome is the number of cases of aspiration pneumonia during this period. Diagnosis of aspiration pneumonia will be performed by the attending physician based on the Japanese Respiratory Society Guidelines for the Management of Hospital-Acquired Pneumonia in Adults. The total number of diagnoses will be calculated at the end of the study.
Secondary outcomes
Secondary outcomes will help determine whether seal acupuncture improves swallowing function and general conditions. The secondary outcomes are LTSR, fever frequency, Barthel index (BI), body mass index (BMI), general blood test analysis, and the Mini-Mental State Examination (MMSE). The LTSR measures the time between the insertion of an 8 Fr tube into the nasal cavity to the uvula of the palate and the initiation of swallowing after the injection of 1 mL of distilled water. A total of three measurements are taken, and the mean value is calculated. Fever is defined as the body temperature of 37.5°C or more. The number of days of fever during the study period will be counted.
Participant timeline {13}
Enrolment
Participants who meet the eligibility criteria and are determined to participate will be enrolled after consultation with their physician.
Assessments
LTSR, BI, BMI, blood test parameters, and MMSE will be measured before starting the intervention. LTSR will be measured one month after the start of the intervention. At the end of the study period, all assessments will be measured. Measurements are allowed 15 days before and after the scheduled date.
Sample size {14}
The calculation of the sample size is based on previous studies. The incidence of aspiration pneumonia in previous studies was 0.091 (4/44) for the intervention group and 0.292 (14/48) in the control group [16]. The sample size was calculated with a two-tailed significance level of 5% and a power of 80%, resulting in a total of 118 participants, 59 in each group. To account for 20 dropout participants, the calculation 118 + 20 = 138 suggests that 138 patients should be recruited. We rounded this value to a total of 140 patients.
Recruitment {15}
Potential participants with cerebrovascular disease with a history of aspiration pneumonia will be recruited from the National Hospital Organization Yonezawa Hospital, Minamisanriu Hospital, Kesennuma City Motoyoshi Hospital, Saka General Hospital, Sendai Tomizawa Hospital, and Ikeno Clinic. The physician will contact the administrator when a patient matches the eligibility criteria. If the participants are interested in our study, they will be told of the purpose and content of research as well as the benefits and drawbacks of participating in detail. After screening, the participants who met the inclusion criteria will be enrolled. The study flow is shown in the SPIRIT Figure (Fig. 1). Participants will undergo a 12-month treatment period.
Assignment of interventions: allocation
Sequence generation {16a}
After obtaining written informed consent from the participants and baseline screening. Random numbers of 001–140 will be automatically generated by the SPSS software (whole random numbers). The participants will be randomly assigned to the intervention group or control group at a ratio of 1:1. An overview of the case distribution of each center, specific measurements, and time points of data collection can be found in the SPIRIT Figure (Fig. 3).
Concealment mechanism {16b}
The random allocation sequence will be stored and concealed from the treating physicians, statisticians, and outcome assessors to prevent detection bias.
Implementation {16c}
The designated statisticians will generate the allocation sequence, and different investigators designated by the project leader will enroll or assign participants.
Assignment of interventions: Blinding
Who will be blinded {17a}
Information including the number of cases of aspiration pneumonia, LTSR, fever frequency, BI, BMI, general blood sampling, and the MMSE will be assessed by independent assessors who are blinded to the assignment and treatment. The principal investigators, statisticians, and outcome assessors will be blinded to the treatment assignments until the database is locked.
Procedure for unblinding if needed {17b}
Unblinding the investigators will be permissible only in specific situations, such as when knowledge of the actual treatment is highly necessary for the appropriate management of participants (e.g., serious adverse events).
Data collection and management
Plans for assessment and collection of outcomes {18a}
An overview of specific measurements and time points for data collection can be found in the SPIRIT Figure (Fig. 3). After meeting the participant, all data will be recorded in detail in the case report form (CRF) of the medical record. At each assessment, an investigator from the institution will be responsible for examining each patient. Information on the baseline number of cases of pneumonia in the past three months, medical history, and previous medications will be collected only during the initial interview.
Plans to promote participant retention and complete follow-up {18b}
Communication will be frequent with the attending physician at each center to facilitate participant retention.
Data management {19}
A third person (data manager) will independently check and judge the input data. The principle investigators from each of the trial sites will confirm whether all CRFs have been timely completed and ensure that the withdrawal of participants and all adverse events are documented in the CRFs. All original data and relevant records will be properly classified and stored at each study center under confidential conditions for 3 years.
Confidentiality {27}
Participants’ personal information will be kept confidential in the same way as their medical records in the hospital before, during, and after the trial.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Not applicable.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Statisticians will independently undertake statistical analysis. Parametric data will be presented as mean ± standard deviation (SD), while non-parametric data as median and 95% confidence interval (95% CI). Two-tailed t-tests and chi-square tests will be used to compare the demographic and clinical characteristics of the two groups at baseline. MMSE, BI, and total caloric intake at baseline and endpoint will be compared between the two groups using repeated measures analysis of variance (ANOVA). Febrile days of the two groups will be compared using the two-tailed t-test. The probabilities of being pneumonia-free and survival from pneumonia-related death will be estimated using the Kaplan-Meier product-limit method. Pneumonia-free and survival rates will be calculated from the date of random assignment to the date of pneumonia onset, date of death, or cutoff date for patients alive at the time of closure of the dataset. A Cox proportional hazards regression model will be used to examine the relationships between modifiable factors and incidence of pneumonia or pneumonia-related mortality. Relative risks (RRs) and 95% confidence intervals (CIs) will be calculated to assess response rate. Number needed to treat pneumonia will be calculated from two-by-two tables. Plausible predictors (age, sex, ease of diagnosis, duration of illness, activities of daily living ability, cognitive function, and treatment assignment) will be included in the original model. Backward stepwise regression will be performed, and P > 0.2 will be used for variable removal. Statistical analysis will be performed using SPSS 21.0 software (IBM, Armonk, USA). All statistical tests will be two-sided tests, and the statistical significance threshold will be set at 5%.
Interim analyses {21b}
No interim analysis is planned.
Methods for additional analyses (e.g. subgroup analyses) {20b}
No additional analysis is planned.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
If missing values are encountered, multiple imputation will be used to obtain the final data. The primary analysis will use intention to treat (ITT) to assess whether a clinical intervention using a press needle has an impact on the incidence of aspiration pneumonia in the intervention and control groups.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
Not planned in this study.
Oversight and monitoring
Composition of the coordinating center and trial steering committee {5d}
The principal investigator will ask the chief audit officer to conduct an audit for the purpose of improving the scientific and ethical quality of the research.
The investigators will prepare a written audit plan and, based on this, visit the institution to check the approval documents by the head of the institution, review the explanatory and consent documents, and check the contents of the CRFs against the medical records.
The results of the audit will be submitted to the principal investigator, principal investigator of the institution, and head of the institution.
Composition of the data monitoring committee, its role and reporting structure {21a}
The principal investigator will ask the data controller and monitoring personnel to monitor the study to ensure that the study is being conducted safely and in accordance with the research protocol with accurate data collection.
The principal investigator will prepare a monitoring plan, and the data controller and monitoring staff will conduct the monitoring in accordance with the monitoring plan.
The data controller and the monitoring personnel will submit a monitoring report to the principal investigator.
Adverse event reporting and harms {22}
Adverse events such as signs and symptoms and other discomfort, will be observed and recorded in detail during the study. The attending physician will take appropriate action in the event of a serious adverse event/failure and report it to the principal investigator of the institution. The principal investigator will review information regarding (1) the type of the adverse event, (2) the severity classification, (3) the severity and the reason for the determination of severity, (4) predictability, (5) the causal relationship with the intervention, (6) the history of the event, and (7) the identification of the participant. The severity classification will be determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.0: http://www.jcog.jp/doctor/tool/CTCAEv4J_20150310.pdf).
Frequency and plans for auditing trial conduct {23}
The study will be audited every six months from the first participant’s enrollment date..
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
If there are changes to the eligibility criteria, outcomes, and analyses, a new version of the protocol will be submitted to the Tohoku University Hospital Ethics Committee for approval.
Dissemination plans {31a}
Research results will be presented in the form of papers and conference reports.