Acupuncture for Prostatectomy Incontinence: Study Protocol for A Multicenter Single Blind Randomized Parallel Controlled Trial

Yao Zhang First Teaching Hospital of Tianjin University of Traditional Chinese Medicine Shanqi Guo First Teaching Hospital of Tianjin University of Traditional Chinese Medicine Chaoran Wang Tianjin University of Traditional Chinese Medicine Xiaodi Liu Tianjin University of Traditional Chinese Medicine Yan Liu Beijing University of Chinese Medicine A liated Dongzhimen Hospital Hongcai Shang Beijing University of Chinese Medicine A liated Dongzhimen Hospital Peiying Yang First Teaching Hospital of Tianjin University of Traditional Chinese Medicine Liang Wang Tianjin Medical University General Hospital Jingbo Zhai Tianjin University of Traditional Chinese Medicine Xiaojiang Li (  zxqlovelxj@126.com ) First Teaching Hospital of Tianjin University of Traditional Chinese Medicine Yingjie Jia (  jiayingjie1616@sina.com ) First Teaching Hospital of Tianjin University of Traditional Chinese Medicine


Background
Prostate cancer is one of the most common malignant tumors of the male genitourinary system and radical prostatectomy is the rst-line treatment for localized prostate cancer [1]. Prostatectomy incontinence (PPI) is a known complication with an incidence rate ranging from 4-31% [2], which has a signi cant impact on men's quality of life (QoL) [3][4]. The complication may generate feelings of low self-esteem, anxiety, and depression. The patients' shame and discomfort arises from the inability to control the bladder. Patients who do not wish to wear a diaper daily, but always carry it for safety in their bag when leaving home [5]. The present study revealed that the postoperative period of 2 to 6 months had a severe impact on their QoL [6].
The treatments for PPI are mainly divided into two types. Conservative treatment includes bladder or pelvic oor muscle training [7][8], biofeedback [9][10], and drug therapy [11][12]. Surgical intervention mainly includes arti cial urethral sphincter implantation [13], urethral suspension [14][15], or injection therapy [16]. All these treatments may bene t patients; although, it cannot be denied that anti muscarinic drugs such as duloxetine are often accompanied by symptoms of insomnia, nausea, loss of appetite, irritability, and other side effects [17,18]. Further, surgical interventions are traumatic forms of treatment, and are also costly [19]. Pelvic oor muscle training is the most used conservative treatment for urinary incontinence, but for elderly male patients with prostate cancer, whether functional training is carried out correctly is di cult to evaluate and assess, and it is challenging to implement. Acupuncture, as a typical treatment modality of traditional Chinese medicine (TCM) [20,21]. With few adverse effects, TCM may be used as an alternative treatment approach for patients. Many research centers, mostly in China, have conducted clinical trials to evaluate the safety and effectiveness of acupuncture in managing post-PPI. Liu et al. [22] conducted a multicenter, randomized clinical trial and revealed that women with stress urinary incontinence can bene t from electroacupuncture involving the lumbosacral region. Chen et al. [23] determined that acupuncture could be bene cial for men with post-PPI when applied alone or as an adjunct to other conservative therapies and medicines. Therefore, acupuncture could be considered an effective treatment for urinary incontinence.
Based on a systematic review [23], acupuncture may be an appropriate treatment for PPI; However, the quality of evidence has been low and inconclusive. Therefore, we plan to perform a multicenter randomized controlled trial (RCT) to investigate the e cacy and safety of acupuncture in the treatment of PPI in patients with prostate cancer.

Study design
This study is a multicenter, single blind, randomized parallel controlled prospective clinical trial with the objective of estimating the e cacy and safety of acupuncture on PPI by comparing a verum acupuncture group with a sham acupuncture group. Participants considered suitable for the study will be randomly allocated into the intervention group (verum acupuncture) or the control group (sham acupuncture) in a 1:1 ratio.

Baseline assessment
A baseline registration will be performed before treatment. Participants will provide a review of basic information, malignancy history including operation history, pathology, and QoL assessment including urinary incontinence. A safety evaluation will also be performed.

Recruitment
We will recruit participants who are attending the 20 above-mentioned hospitals in this trial. We will use WeChat to publish recruitment information, and use the "recruiters" applet to recruit and retrieve information for patients.

Inclusion criteria
Patients who meet all the following requirements will be allowed to enroll: 1. Patients who have received radical prostatectomy with de nite pathological diagnosis of prostate cancer: 2. Diagnosis of urinary incontinence by the International Continuity Society criteria or patients who were evaluated by the urologist as experiencing urinary incontinence resulting from prostate surgery [24]; 3. Karnofsky Score≥60 or Eastern Cooperative Oncology Group (ECOG) Score 0-2; 4. Willing to participate in the study and sign the consent forms.

Exclusion criteria
Patients who meet all the following criteria will be excluded: 1. Urgency urinary incontinence caused by detrusor hyperre exia and bladder spasm, and urinary incontinence caused by central system or endocrine factors; 2. Urinary incontinence treated by cystostomy, urethral sphincter reconstruction, or urethral suspension; 3. Currently receiving less than 6 months treatment similar to acupuncture (such as electroacupuncture, warm moxibustion, warm acupuncture, etc.); 4. Irreversible urinary incontinence due to permanent nerve injury and complete loss of function of the external urethral sphincter; 5. Urinary tract infection (except asymptomatic lower urinary tract infection); 6. History of severe arrhythmia, severe cardiac insu ciency, acute myocarditis, constrictive pericarditis, pericardial tamponade, severe valvular disease, heart failure, or other serious heart diseases; 7. History of severe liver injury or potentially severe liver disease (ALT or AST > 10 times normal); 8. History of severe renal impairment (estimated GFR < 25 mL/min/1.73 m 2 ); 9. History of other important organ dysfunction or hematopoietic system disease, or other serious primary diseases(s); 10. Known to coagulation dysfunction (with typical clinical diagnosis or clear laboratory test results); 11. Patients with mental illness or cognitive impairment, or severe depression; 12. Patients who are not suitable to participate in this study or who are likely to withdraw from the study based on the judgment of the researchers; 13. Patients participating in other clinical trials.
Withdrawal from the study Participants will be allowed or asked to withdraw from the study in the following circumstances: 1. Patients who express an unwillingness to being subjected to the assigned treatment for various reasons at any stage of the trial; 2. Patients experience an adverse events (AE) that necessitates their withdrawal from the trial; 3. Patients who cannot fully participate in the treatment or follow-up period; 4. Patients can withdraw from the study voluntarily for any reason.

Randomization and blinding
A total of 340 participants will be randomly allocated into the treatment group or the control group. Each hospital will recruit 17 patients. In this trial, we will carry out block randomization in a 1:1 ratio according to the sequence generated using SAS software version 9.4 (SAS Institute Inc. Cary, NC). Random allocation will be performed after eligible participants consent in written form and complete baseline assessments. The participants, outcome assessors, and statisticians will be blinded to treatment allocation. The acupuncturist will not be blinded to the participant's allocation. All participants in the study will sign a con dentiality commitment to avoid blind disclosure.

Ethics
The study will be performed in accordance with the principles of the Declaration of Helsinki, and has been approved by the ethics committee boards of the participating hospitals. Written informed consent will be obtained from each subject before the patients are enrolled in the trial. Ethical approval is provided as Additional le 1.

Interventions
According to the predetermined randomization results, participants will be randomly allocated to the verum or sham acupuncture group. All participants will go through a standardized interview, which will be recorded on the case report forms. To minimize bias, all the acupuncturists in this trial are specialists in acupuncture. They have a minimum of 2 years' experience in acupuncture treatment and hold licenses to perform acupuncture. Before performing this trial, all acupuncturists will receive special training regarding the purpose and content of the trial, treatment strategies, and quality control. The owchart and study design schedule are presented in Figure 1 and Table 1, respectively.
The trial will last 24 weeks, including treatment and follow-up periods. All participants will receive treatment for 6 weeks. Participants in both groups will receive verum or sham acupuncture three times a week (recommended interval of one day). Each acupuncture session requires approximately 20 minutes to perform. Sterile needles for single use (0.25×40 mm; Jiangsu Medical Supplies Factory Co., Ltd.) will be used in this study. Needles in the treatment group will be inserted at a depth of 0.8-1 inches and manually manipulated by rotation methods. After acupuncture, the patient's "De Qi" should be taken as the criterion (the feeling of pain and numbness). In the control group, needles will be inserted about 0.5 inch in depth, and will not receive further manipulation. To prevent blind uncovering, the operator will pay attention to the depth and angle of the shallow stab. All participants will be evaluated by blind method at week 6 after acupuncture. The Blind Method Assessment is shown in Additional le 2. 12. SAS: Self-Rating Anxiety Scale is a 20-item self-report assessment;

Sham acupoints used in the control group
To ensure the quantity of stimulus is uniform between two groups, the same kind, size, and number of needles will be used for the control group. However, the control group will be treated with shallow needling at the non-meridian and non-acupoint positions. The acupuncture points shifted 1-inch from the actual location and have no therapeutic value.

Permitted and prohibited concomitant treatments
Both groups can receive conventional treatment for prostate cancer (such as endocrine therapy) and/or pelvic oor muscle training, which differ from acupuncture principles. Researchers need to keep a detailed record. Treatments like the principles of acupuncture are not allowed.

Outcome measures
Primary outcome measures ICIQ-UI-SF The International Consultation Incontinence Questionnaire-Urinary Incontinence Short Form. Scores of the scale will be calculated to investigate the incidence of urinary incontinence and the impact of urinary incontinence on patients. It will be used at baseline, and at weeks 6, 12, 18, and 24. The scale is shown in Additional le 4.
Secondary outcome measures 1-h Pad Test It is a test to objectively evaluate urinary incontinence. It is measured to assess the change in volume of urine leakage from baseline at weeks 4 and 6.
72-hour Voiding Diary On the basis of not changing life status and urination habits, 72 hours of uid intake and urination time are continuously recorded every week. It is used to assess the change in mean 72-hour incontinence-episode frequency (IEF) from baseline, and at weeks 1, 2, 4, 6, 12, 18, and 24. The scale is shown in Additional le 5.
EPIC-26 The Expanded Prostate Cancer Index Composite 26-item version includes three categories of questions aimed to evaluate the prostate function and QoL of patients with prostate cancer in the past 4 weeks. Evaluated at weeks 6, 12, 18, and 24, changes in scores from the baseline will be analyzed. The scale is shown in Additional le 6.
SAS Self-Rating Anxiety Scale is a 20-item self-report assessment used to measure anxiety levels, based on the scoring of 4 groups of symptoms: cognitive, autonomic, motor, and central nervous system symptoms. The scores will be evaluated at weeks 6, 12, 18, and 24, and changes in scores from the baseline values will be analyzed. The scale is shown in Additional le 7.
Weekly consumption of pads Changing and average weekly consumption of pads at weeks 1, 2, 4, 6, 12, 18, and 24 from the baseline will be calculated.
Severity of urinary incontinence It will be evaluated at weeks 6, 12, 18 and 24. The change in the number and percentage of severity ratings from the baseline value will be analyzed.
Self-report assessment of therapeutic effect A 4-point scale is used: no help, little help, medium help, and great help [25]. Treatment effects will be evaluated at weeks 6, 12, 18, and 24.

Safety assessment
To exclude any related serious diseases, patients will be asked to undergo necessary inspection before randomization, including vital signs, blood routine, urine routine, biochemical items, ECG. These tests will be performed at the week 6 of the study to evaluate the safety of this trial. If any AEs occur during the trial, patients will be treated as soon as possible.
Statistical methods

Sample size calculation
By enrolling approximately 340 (170 in each group) participants, the study will provide 90% power to detect a between-group difference of 2.5 in reduction of ICI-Q-SF score from baseline using a 2-sided alpha level of 0.05, and assuming a common standard deviation of 6.3 and a dropout rate of 20%. A difference of 2.5 points in the ICI-Q-SF score was selected for sample size calculations, which is indicative of a clinically signi cant change [25][26][27].

Statistical analysis
Summary tables (descriptive statistics and/or frequency tables) will be provided for all variables as appropriate. The primary outcome analysis will use the Cochran-Mantel-Haenszel (CMH) test. For continuous variables, means and standard deviations will be presented, unless the variable has a skewed distribution, in which medians, 25th and 75th percentiles will be presented. For other categorical data, between group comparisons will be performed using a Wilcoxon rank-sum test, chi-square test, or Fisher's exact test, as appropriate. AE incidences for each treatment group will be tested by the c2 test or Fisher's exact test as appropriate. All the statistical analysis will be performed using SAS version 9.4 (SAS Institute Inc) with 2-sided tests at a signi cance level of <0.05.

Discussion
PPI has a signi cant impact on the QoL of patients who undergo prostatectomy. It is closely associated with the trauma caused by surgery [28,29]. Although urinary incontinence after prostate cancer heals within half a year, the need for active improvement of symptoms and the QoL of patients is widely recognized [30]. Surgical resection of prostate cancer mainly includes bladder neck, bilateral vas deferens ampulla, bilateral seminal vesicles, and the intact prostate. Although a complete resection of the tumor and avoidance of positive surgical edge can be achieved, often the bladder neck and part of the prostatic apex urethra are removed, which will lead to damage of the urinary control structure. In addition, due to intraoperative bleeding, tumor in ltration, and adhesion, the distal sphincter, fascia, ligament, and pelvic oor muscles may be damaged, which leads to postoperative urinary incontinence [31,32]. The e cacy of acupuncture has been proved by many RCTs [33]. A systematic review demonstrated that acupuncture was an appropriate adjunctive therapy for PPI, but the supporting evidence was not su cient. These limitations included small sample size, greater-than-anticipated withdrawal, the lack of a control group, and unclear statements about randomized allocation. Therefore, more powerful evidence is still needed to verify the e cacy and safety of acupuncture for PPI. We have presented the design of a RCT of verum acupuncture compared with sham acupuncture. Completion of this trial will contribute to verifying the e cacy of acupuncture for the treatment of PPI. This multicenter study covers 13 provinces and cities from south to north in China, we hope that the results will provide robust evidence to support the application of acupuncture in the treatment of postoperative incontinence of prostate cancer.

Declarations
Ethics approval and consent to participate: The trial has passed the ethical application, and the participants signed an informed consent form.
Competing interests: The authors declare that they have no competing interests. And agree to public the protocol and follow-up research data.  Trial owchart. UI urinary incontinence; PC prostate cancer; PPI prostatectomy incontinence.

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download.