Study setting {9}
The three groups are active control group: PFMT, twice per week for 5 weeks; Group 1 (low-frequency magnetic stimulation group): PFMT + electromagnetic stimulation, twice per week for 5 weeks, every 2 sessions will be separated by at least 48 hours; Group 2 (high-frequency magnetic stimulation group): PFMT + electromagnetic stimulation, continuous treatment for 10 days. All the patients will also receive a 3-month post-intervention follow-up. The randomization process will be conducted by an online random number generator. The random numbers will be kept in opaque envelopes. Then, a research assistant will allocate the numbers to the participants according to the order of inclusion. The present study cannot blind the practitioner and the participants due to the nature of the interventions. However, the outcome assessor and data analyst will be blinded.
Eligibility criteria [1]
Inclusion criteria
- Women aged 18-75 years.
- Women who report at least 3 episodes of involuntary urine leakage weekly during the preceding 3 months. [14]
- Types of UI will be confirmed by the Questionnaire for Incontinence Diagnosis. [15]
Exclusion criteria
- Body mass index ≥ 35 (equals weight in kilograms divided by height in meters squared).
- Restricted body movement.
- Pelvic Organ Prolapse Quantification System >stage 2.
- History of pelvic surgery or physiotherapy.
- Use of medication for UI or affects skeletal muscle function.
- History of electromagnetic stimulation therapy for UI.
- Neurological diseases.
- Pregnancy.
- Metal implants in the body, such as a pacemaker.
- Other risk factors or comorbidities that interfere with the study.
Who will take informed consent? {26a}
Female patients aged from 18 to 75 who report weekly involuntary urine loss of three or more episodes for the past three months will be included, such criteria have been used widely in previous RCTs on UI. [14] Then, the validated Questionnaire for Incontinence Diagnosis (QUID) will be applied to confirm the type of UI as a pattern of stress/mixed UI. The eligible participants will be provided written informed consent with information illustrating the purpose and the detailed procedures of the present study after they meet the eligibility criteria. The consent will be obtained by the obstetricians and will be kept confidential and aimed only at research purposes. Data collected will be stored in a locker at the principal investigator’s office, and an electronic version will be protected by a password on the hospital computer.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
No biological specimens will be collected from this study. If additional data or biological specimens are required, they must be authorized by ethical boards and be included in the consent.
Interventions
Rationale for the choice of comparators {6b}
The participants in the active control group will receive PFMT, which is recommended as the first-line therapy for UI [7]. Patients with UI are usually informed to do PFMT at home or under supervision by physiotherapists.
Intervention description {11a}
All the participants in the three groups will receive PFMT. The efficacy of PFMT has been reported widely in improving or curing UI in all age groups. [16] International Continence Society published the guideline on managing incontinence and suggests that supervised PFMT should be considered as the first-line treatment for stress and mixed UI in women. [17] Due to the consideration of manpower and financial resources, the evidence from the GROUP study showed that the group-based PFMT can also demonstrate similar effects for the treatment of UI when compared with supervised individual PFMT. [14] To maximize the effect of PFMT and the patient’s adherence, the psychological self-determination theory (SDT) will be embedded in this treatment program. [18] SDT has been widely adopted in the literature on exercise behavior, and it assumes that all humans possess three psychological needs: a need for autonomy, a need for relatedness and a need for competence. [19] Rationale of the PFMT will be provided for the patients, as well as clear goals with feedback and interpersonal interaction. All the above-mentioned SDT strategies have no direct effect on UI.
Each electromagnetic stimulation session consists of 10-min electrical and 20-min magnetic stimulation. Electrical and magnetic stimulation device (B4P electrical stimulator and MTS magnetic stimulator, Nanjing Medlander Medical Technology Co., Ltd.) will be applied for delivering the intervention. Details of the intervention are illustrated below (table 1). All the uro-physiotherapists will be trained before the initiation of the study to ensure the delivery of standardized treatment procedure. The standardized procedure includes the delivery of PFMT and the manipulation of the electrical and magnetic stimulation device.
Active Control group
Trained uro-physiotherapists will help the patients to initiate the PFMT program. At the beginning of the first session, the uro-physiotherapists will inform the patients of the history of PFMT and its benefits. Patients will be trained in a group of 6-8patients. Before the training, clear goals for each session and the program as a whole will be given to all the patients. After each training session, the patient will fill out a treatment checklist and give suggestions related to the training. Uro-physiotherapists will then provide written/oral feedback for the patients on their improvement and concerns about their training. All the uro-physiotherapists will meet with the research team to ensure the consistency of the training protocol and discuss the concerns that may occur during the delivery of the training. The PFMT program meets the American College of Sports Medicine principles for prescribing exercise, including frequency, intensity, time, type, volume and progression. [20] Patients in the active control group will receive PFMT twice per week for 5 weeks, making a total of 10 sessions. Every two sessions will be separated by at least 48 hours. Each session lasts 50 minutes with a target of increasing pelvic floor muscle strength, power, endurance and coordination in daily life context. The detailed training protocol will follow the Consensus on Exercise Reporting Template (CERT). [21] It provides a direction for reporting exercise-related interventions regardless of exercise type and includes 16 items under 7 domains: what; who; how; where; when; dosage; tailoring; and compliance.
Group 1 (Low-frequency electromagnetic stimulation)
Both electrical and magnetic stimulation is widely applied by the department of Obstetrics and Gynecology as well as pelvic floor rehabilitation clinics for incontinence treatment. All the treatment will take place in a private environment. For the electrical stimulation section, patients will be asked to take off their pants, and then lie on the treatment couch in the lithotomy position. After disinfection and the application of lubricating gel, a J-shape electrode will be placed into the vagina by an experienced uro-physiotherapist. The electrode is connected to a computer that controls the output of the current. The Group 1 patients will receive the treatments with a frequency of 20-60 Hz, pulse width of 200-600 μs. At the same time, to ensure that the patients do not suffer from any pain from electrical stimulation, the treatment amplitude will be adjusted according to the patient’s tolerance to the stimulation. After 10 min of electrical stimulation, patients will be asked to sit ona magnetic stimulation chair. A magnetic coil that can generate a magnetic field will be placed within the treatment chair’s seat. The magnetic coil will be controlled by an external power unit by the same therapist that delivers electrical stimulation therapy. The output of the magnetic stimulation consists of 15Hz for 2s and 30Hz for 3s, with a rest interval of 5s, making up a total treatment period of 20min. The treatment frequency will be 2 sessions per week for 5 weeks, a total of 10 sessions will be initiated. Every two sessions will be separated by at least 48 hours. After the electromagnetic stimulation, patients will complete a 20 min PFMT session, which will be the same as the active control group.
Group 2 (High-frequency electromagnetic stimulation)
Previous studies showed that low-frequency electromagnetic stimulation (twice or three times per week) has demonstrated efficacy in treating UI. [22, 23] However, one study showed that electrical stimulation was no more effective compared with sham treatment, which was controversial with other studies. [24] High-frequency electromagnetic stimulation refers to a regimen that uses a continuous daily treatment protocol, which have also demonstrated safety and efficacy in the treatment of UI. [25, 26] Another advantage of High-frequency electromagnetic stimulation is that patients can focus on the treatment and complete the entire course of treatment in a short period, with similar treatment effects compared with low-frequency electromagnetic stimulation. In the present study, we will adopt a ten-day, daily treatment regimen to match the total treatment volume with group 1. Each treatment session will be the same as group 1, to compare the effects of different treatment frequencies.
Table 1 Standardization of training and protocols
Group
|
Standardized training program
|
Detailed dosage
|
Time in total
|
Active control group
|
Sustained contractions
|
Patients complete PFMT by themselves, 6-10s for each contraction, every two contractions are separated by a period of 10s-rest. 8-10 reps per set for 1-2 sets.
|
50min
|
Phasic contractions
|
The patient completes pelvic floor muscle contractions of 2-5 seconds each, followed by rest intervals of 4-10 seconds. Each set contains 10 contractions, 1-3 sets each.
|
Training guidance
|
Under the guidance of the instructor, patients perform PFMT, combined with breathing and relaxation training.
|
Group 1
|
PFMT + electromagnetic stimulation
|
PFMT is the same as the active control group.
Electrical stimulation: 20-60 Hz, the pulse width of 200-600 μs, 10 min of stimulation.
Magnetic stimulation: 15Hz for 2s and 30Hz for 3s, with a rest interval of 5s, 20 min of intervention.
Twice per week for 5 weeks.
|
|
Group 2
|
PFMT + electromagnetic stimulation
|
PFMT is the same as the active control group.
Electrical stimulation: 20-60 Hz, the pulse width of 200-600 μs, 10 min of stimulation.
Magnetic stimulation: 15Hz for 2s and 30Hz for 3s, with a rest interval of 5s, 20 min of intervention.
10 consecutive days.
|
50min
|
Criteria for discontinuing or modifying allocated interventions {11b}
Patients of the study are allowed to withdraw from the study at any time for any reason if they wish to do so without any consequences. The researchers of the study can also discontinue the participation if the participant is uncooperative and does not attend the study visits, and this patient will not be replaced by a new patient.
Strategies to improve adherence to interventions {11c}
To improve the patient adherence, individuals who take participation in the study will be closely supervised by interventionists with feedback for each treatment session. On an institutional level, all the interventionists and the researchers will have discussions on improving the delivery of the intervention and exchange their opinions on a weekly basis. Details of each intervention session will be recorded in a standardized document.
Relevant concomitant care permitted or prohibited during the trial {11d}
Participants who are taking medication for UI or have an impact on skeletal muscle are prohibited from participating in the trial. Participants anticipated likely to wear a pacemaker due to a cardiac issue are also prohibited from enrolment. The research team will establish good palliative and emergency care management in case of any potential life-threatening issues.
Provisions for post-trial care {30}
The aim of the trial is to establish a comprehensive and standardized program for UI and the participants will be able to continue beyond the trial. According to previous research, the trial does not include any specific risks, there will be no provisions for compensation.
Outcomes {12}
The primary outcome of the study is the International Consultation on Incontinence Questionnaire–Short Form (ICIQ-SF). [27] It is a widely used 4-item questionnaire with full validation that assesses the voiding frequency, voiding volume, impact on quality of life and the cause of leakage during the past 4 weeks. The total score of the questionnaire ranges from 0 to 21, with 0-7 representing mild UI, 8-12 representing moderate UI and 13-21 representing severe UI.
The secondary outcomes include (1) 3-day bladder diary, which record the micturition frequency, incontinence episodes, fluid intake, times of voiding, voided volume, and pad usage per 24 hours for 3 days. Previous observational studies have demonstrated the reliability and reproducibility of data from bladder diaries and standard symptom evaluation. [28] Duration of the diary between three and seven days is usually reported in the literature, while the present study plans to apply the 3-day voiding diary due to the consideration of patients’ compliance and convenience. (2) Pelvic floor muscle function, which includes the modified Oxford Grading Scale, pelvic floor electromyography and pressure measurements. With high inter- and intra-rater reliability, [29, 30] the modified Oxford Grading Scale allows the quantification of pelvic floor muscle strength as 0, no contraction; 1, flicker; 2, weak; 3, moderate; 4, good; and 5, strong. The Glazer protocol embedded electromyography assesses the muscle activities during different stages such as baseline rest, phasic contraction, tonic contraction, endurance contraction and post-contraction rest. The results of the test could reflect the supportive, sexual and sphincter function of the pubococcygeus muscle. [31] Pressure measurement is another traditional way to assess pelvic floor muscle function, along with Oxford Grading Scale and electromyography, this multidimensional assessment model allows for a more comprehensive evaluation of pelvic muscle function. (3) Pelvic organ prolapse quantification (POP-Q) system, which is widely used in clinical settings and provides the characterization of a woman’s prolapse. The detailed technique of performing a POP-Q test has been described in the ICS/IUGA statements. [2, 32] (4) SF-12 health survey, which is one of the most widely used instruments that assess self-reported health-related quality of life. Compared to the original version SF-36, [33] the SF-12 covers all 8 domains with fewer questions, which makes it more practical for patients to complete. Meanwhile, the Chinese version of SF-12 has been validated, which has similar psychometric properties as the English version. [34]
Project timeline {13}
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)
Sample size {14}
The present study intends to apply ICIQ-SF as the primary outcome. After calculation, a sample size of 44 in each group is able to provide 80% power to detect a within-between group difference measured using ICIQ-SF at three time points, assuming a small effect size (Cohen’f) of 0.125 and a 2-sided significance level of 5%. Considering that there is a 20% dropout rate, the study will increase the sample size to 165 in total.
Recruitment {15}
Female patients who report at least 3 episodes of involuntary urine leakage weekly during the preceding 3 months will be recruited. A poster will be posted on the bulletin board to illustrate the study details including the research background, criteria for enrollment, potential benefits of the intervention and other rights of the participants. Patients who meet the inclusion criteria of the study will be given the information sheet, and researchers of the study will demonstrate the details of the study to the patients. Those who have an interest in joining the study will sign the consent forms.
Assignment of interventions: allocation
Sequence generation {16a}
After confirming the consent, statistical program R will be applied to generate a randomization sequence. The allocation will be carried out by a research assistant who has no role in delivering the intervention and the data analysis. All the participants will be allocated in a 1:1:1 ratio.
Concealment mechanism {16b}
A circulating nurse who will not take part in this trial will be able to get access to the online randomization database. The investigator will be informed by the nurse that the participant is in the active control group or intervention groups.
Implementation {16c}
After signing the informed consent forms, participants will be allocated to one of the study arms according to the sequence. The study group will also be revealed at the same time to the participants and the researchers of the study.
Assignment of interventions: Blinding
Who will be blinded {17a}
As the present trial is open-labelled, all the participants will not be blinded due to the major difference between the two groups (frequencies of the treatment and whether electromagnetic stimulation will be delivered)
Procedure for unblinding if needed {17b}
The study does not include any unblinding procedure as this is an open-labelled trial. How about the outcome assessors? You can still name this study as single-blinded.
Data collection and management
Plans for assessment and collection of outcomes {18a}
All the data will be collected at baseline, how about at the end of the high-frequency group intervention? at the end of week 5, and 3 months after the intervention. A training diary will be given to all the individuals to record their treatment, including training frequency, total time of each meeting, parameters of each stimulation session and the sum of the treatment time. The aim of this strategy is to ensure that the total volume of the treatment remains the same. The interventionist will record the treatment after each session, making sure that the PFMT and the electromagnetic stimulation protocols remain constant across the treatment. Validation study of the primary outcome, ICIQ-SF, shows that it is significantly related to the Patient Global Impression of Improvement and the 24-hour pad test. [35] All the patients will be informed not to take bladder medicine for at least 2 weeks before completing the 3-day bladder diary. The patients will also be asked not to alter their habits of fluid intake and retain their voiding habits during the trial. The urine output will be measured using calibrated cups, and the recording will begin at 8 am and end at 7:59 am the next day. [36] These along with other secondary outcomes will be collected at baseline, at week 5 and after 3 months.
Plans to promote participant retention and complete follow-up {18b}
Before and during the intervention, participants will be given extensive information related to the importance of electromagnetic and PFMT for UI. Participants are allowed to discontinue at any time point of the study without giving a reason. However, if possible, these participants will also be asked to provide the outcomes of the study at week 5 and follow-up. Questionnaires, bladder diary and pelvic floor muscle function are routinely applied in urology outpatient and are characterized by efficient and convenient.
Data management {19}
An (electronic case report form) eCRF will be applied to record the data. Data of included participants will be entered into a web-based system Ennov Clinical ® 7.5.720. Participants will be identified using the inclusion number, the first letter of their family name and their given name. This eCRF will be kept by the coordination site of the study. All the data will be entered twice by two individual research assistants.
Confidentiality {27}
The full name of each participant and the identification code will be stored in a document kept by the principal investigator. Only the research team can get access to the key to the document. Participants’ private data will not be reported in the publication.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
No biological specimens will be collected in the trial. Questionnaires and electromyography data will be kept in the hospital’s online system as routine clinical assessment and may be used for future cohort studies.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
The main analysis will follow the intent-to-treat principle with all the randomized patients included. The present study will keep the missing data missed and will not replace them. Normally distributed variables will be presented as mean (SD) values. Non-normally distributed continuous variables will be reported as medium values with interquartile ranges (25th-75th percentile) and percentages will be used for categorical variables. Shapiro-Wilk test will be used to examine the normal distribution of the variables.
Baseline demographic data will be reported for all patients randomized to the three groups. These data include patients’ age, education level, employment, annual household income and medical history (BMI, ever pregnant, cigarette smoking and diabetes). Baseline data will be evaluated by χ2 or Fisher’s exact for categorical variables and Analysis of Variance (ANOVA) for continuous variables and the Kruskal-Wallis test for non-parametric variables.
Generalized estimation equation (GEE) models will be applied to analyze primary and secondary outcomes collected at different time points. Considering the potential effects of age, BMI, severity of UI and other variables on the outcomes, subgroup analysis will be carried out to evaluate whether age (</≥50 years), the severity of UI (ICIQ-SF </≥13 points),BMI (</≥25 kg/m2) at baseline could have an impact on the effect of the treatment.
Interim analyses {21b}
ICIQ-SF and 3-day bladder diary will be collected at the end of week two as interim analysis.
Methods for additional analyses (e.g. subgroup analyses) {20b}
No subgroup analysis was planned due to the small sample size of the study.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
The main analysis of the study will adopt the intention-to-treat (ITT) method, in which all the patients will be included in the final analysis according to the random allocation regardless of the study completion. Also, generalized estimation equation (GEE) models will be used to analyze outcomes collected at different time points. This approach could fit the outcomes at different time points so all the participants are allowed in the analysis, even if missing data exist. The study will report the rate of missing data, and the missing data will not be replaced.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
We will follow the requirements with regard to submitting the data to the journal where we publish the results of the study. After the publication, the full protocol, participant-level data and statistical code will be available under reasonable request.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The two authors from the Chengdu Women’s and Children’s Central Hospital take full responsibility for conducting the intervention, scientific validity and patient management. All the authors will participate in periodic meetings to discuss the progress of the study and strategies to better manage the trial weekly.
Composition of the data monitoring committee, its role and reporting structure {21a}
The trial is going to be conducted in accordance with the Good Clinical Practices and Chinese regulations. The present study does not declare a data and safety monitoring board as electromagnetic stimulation and pelvic floor muscle training are both regarded as low risk and have been used routinely in patients who need medical care urgently.
Adverse event reporting and harms {22}
Any adverse events (AEs) will be reported to the study staff and the ethics committee of the Chengdu Women’s and Children’s Central Hospital. The AEs will be managed by the physician in charge of the participant’s care.
Frequency and plans for auditing trial conduct {23}
The audit of the trial will be performed weekly by a member designated by the sponsor of the study and will be independent of the study steering committee, the sponsor and the investigators.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Any revision to the trial will be reported to the ethics committee and the trial registry. After receiving the approval of the protocol revision, we will communicate them to the study participants, the sponsors and the investigators.
Dissemination plans {31a}
The trial is registered on chictr.org.cn with the reference number ChiCTR2200061035. The results of the study will be published in a peer-reviewed medical journal. The investigator will also communicate the trial results to the national and international scientific community and healthcare providers at different conferences.