Efficacy and Safety of High Dose Vitamin D Supplementation for Overactive Bladder Dry in Children: A Randomized Clinical Trial
Phase: NA
Conditions: Overactive Bladder
Sponsor: Xing Liu

Efficacy and Safety of High-Dose Vitamin D Supplementation for Overactive Bladder Dry in Children: 
 A Randomized Clinical Trial (Edition Number:3) 
 
 
Efficacy and Safety of High-Dose 
Vitamin D Supplementation for 
Overactive Bladder Dry in Children: 
A Randomized Clinical Trial 
  
Sponsor: Children’s Hospital of Chongqing Medical University  
Principal Investigator: Xing Liu, MD, Professor of Pediatric 
Urology, Chongqing Medical University  
Supported by: The National Natural Science Foundation of China 
and the Program for Youth Innovation in Future Medicine at 
Chongqing Medical University 
 
 
Trial Protocol   
Study Number:2022515 
Edition Number:3 
Version Date: 10/20/2022 
No support is provided by pharmaceutical companies or device manufacturer 

Efficacy and Safety of High-Dose Vitamin D Supplementation for Overactive Bladder Dry in Children: 
 A Randomized Clinical Trial (Edition Number:3) 
 
 
Efficacy and Safety of High-Dose Vitamin D Supplementation for Overactive 
Bladder Dry in Children: A Randomized Clinical Trial 
1. STUDY OBJECTIVES ...................................................................................... 1 
2. BACKGROUND AND RATIONALE ................................................................... 1 
3. STUDY DESIGN. ............................................................................................ 4 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS. ....................................... 5 
4.1 Inclusion Criteria .............................................................................................. 5 
4.2 Exclusion Criteria .............................................................................................. 6 
4.3 Study Enrollment Procedures ............................................................................ 7 
5. STUDY INTERVENTIONS ............................................................................... 7 
5.1 Interventions, Administration, and Duration ..................................................... 7 
5.2 Adherence Assessment ..................................................................................... 8 
6. STUDY PROCEDURES. ................................................................................... 8 
6.1 Schedule of Evaluations .................................................................................... 8 
6.2 Description of Evaluations ................................................................................ 9 
6.2.1 Screening Evaluation ..................................................................................................... 9 
6.2.2 Enrollment, Baseline, and/or Randomization ............................................................ 10 
6.2.3 Blinding ........................................................................................................................ 11 
6.2.4 Follow-up Visits ........................................................................................................... 11 
6.2.5 Completion/Final Evaluation ...................................................................................... 11 
7. SAFETY ASSESSMENTS ............................................................................... 12 
7.1 Specification of Safety Parameters .................................................................. 12 
7.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters
 .................................................................................................................................... 12 
7.3 Adverse Events and Serious Adverse Events .................................................... 13 
7.4 Reporting Procedures ..................................................................................... 13 
In the event of any adverse event, investigators will be notified within 24 hours. . 13 
7.5 Followup for Adverse Events ........................................................................... 13 
7.6 Safety Monitoring ........................................................................................... 13 
8. INTERVENTION DISCONTINUATION ............................................................ 13 
9. STATISTICAL CONSIDERATIONS ................................................................... 14 
9.1 General Design Issues ..................................................................................... 14 
9.2 Sample Size and Randomization ..................................................................... 15 
9.3 Definition of Populations ................................................................................ 17 
9.3.1 Intention-to-treat (ITT) analysis .................................................................................. 17 
9.3.2 Per protocol (PP) analysis set ...................................................................................... 18 
9.3.3 Safety analysis set ....................................................................................................... 18 
9.4 Interim Analyses and Stopping Rules .............................................................. 19 
9.5 Outcomes and data Analyses .......................................................................... 19 
9.5.1 Primary Outcome ........................................................................................................ 20 
9.5.2 Secondary Outcomes................................................................................................... 21 
9.5.3 Safety analysis ............................................................................................................. 24 

Efficacy and Safety of High-Dose Vitamin D Supplementation for Overactive Bladder Dry in Children: 
 A Randomized Clinical Trial (Edition Number:3) 
 
 
10. DATA COLLECTION AND QUALITY ASSURANCE ......................................... 24 
10.1 Data Collection Forms ................................................................................... 24 
10.2 Data Management ........................................................................................ 26 
10.3 Quality Assurance ......................................................................................... 27 
10.3.1 Training ...................................................................................................................... 27 
10.3.2 Protocol Deviations ................................................................................................... 28 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY .......................................... 28 
11.1 IRB Review ................................................................................................... 28 
11.2 Informed Consent Forms............................................................................... 28 
11.3 Participant Confidentiality ............................................................................ 29 
11.4 Study Discontinuation................................................................................... 29 
11.5 Monitor ........................................................................................................ 29 
12 AUDITS ..................................................................................................... 30 
14. REFERENCES ............................................................................................ 30 
15. SUPPLEMENTS ......................................................................................... 34 
 
 
 

Efficacy and Safety of High-Dose Vitamin D Supplementation for Overactive Bladder Dry in Children: 
 A Randomized Clinical Trial (Edition Number:3) 
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Efficacy and Safety of High-Dose Vitamin D Supplementation for Overactive 
Bladder Dry in Children: A Randomized Clinical Trial 
1. STUDY OBJECTIVES  
The purpose of this study was to assess the clinical efficacy and safety of high-
dose Vitamin D Supplementation (VDS) in combination with Standard Urotherapy (SU) 
for the treatment of Overactive Bladder (OAB) dry among pediatric patients, as 
compared to (1) solifenacin, a commonly utilized anticholinergic medication, combined 
with SU, and (2) SU alone. This study endeavors to contribute to the current 
understanding of the optimal treatment approach for managing OAB dry in this 
population and has the potential to inform clinical decision-making and improve patient 
outcomes. 
2. BACKGROUND AND RATIONALE    
According to the International Children's Continence Society (ICCS), OAB is a 
syndrome that manifests as urinary urgency, frequently accompanied by frequency and 
nocturia, with or without urgency urinary incontinence, in the absence of urinary tract 
infection or any other obvious pathology1. This common and concerning condition can 
affect individuals of all ages2. Approximately, OAB has been identified with a 
prevalence of 5-12% in children aged 5-10 years and 0.5% in older adolescents aged 
16-18 years1. OAB may manifest as either OAB-wet, which is characterized by urgency 
urinary incontinence, or OAB-dry, which is characterized by urgency without 

Efficacy and Safety of High-Dose Vitamin D Supplementation for Overactive Bladder Dry in Children: 
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incontinence2. Furthermore, it is noteworthy that those with OAB, even without urine 
loss, experience a reduced quality of life (QoL) compared to those without this 
condition3. Studies on symptoms related to OAB have revealed that they can 
significantly impact patients' QoL, with OAB-dry being just as distressing as urinary 
incontinence. Despite extensive research, the underlying pathological mechanism is not 
yet fully understood, and its complex etiology has resulted in a variety of treatment 
options4. While behavioral and drug therapies are the primary treatments for OAB, they 
may not be fully effective in curing the condition for all patients.  
The first-line treatment for OAB is SU, which comprises several essential 
components. These include providing patients with information and demystifying their 
condition, instructing them on how to resolve lower urinary tract (LUT) dysfunction, 
offering lifestyle advice, registering symptoms and voiding habits, and providing 
ongoing support and encouragement through regular follow-up sessions with the 
caregiver5. Anticholinergic medications, also known as antimuscarinics, are commonly 
prescribed as the first-line treatment for OAB in children who exhibit persistent 
symptoms despite undergoing SU. Solifenacin succinate is a medication that falls into 
this category and is primarily employed to alleviate symptoms of OAB, such as urinary 
urgency, frequency, and incontinence. Although solifenacin succinate has demonstrated 
efficacy in clinical studies, it may result in common adverse effects, including 
xerostomia, constipation, blurred vision, and headache6,7. These side effects may pose 
a challenge to patients' adherence to medication, particularly during prolonged 

Efficacy and Safety of High-Dose Vitamin D Supplementation for Overactive Bladder Dry in Children: 
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treatment. 
There are two distinct forms of vitamin D in nature: vitamin D3 of animal origin 
(cholecalciferol) and vitamin D2 of plant origin (ergocalciferol). In humans, vitamin D3 
is produced in the skin through exposure to sunlight, whereas vitamin D2 and D3 can be 
obtained from the diet, though only a small number of foods contain substantial 
amounts of the vitamin8,9. Vitamin D2 and D3 are conveyed via vitamin D-binding 
proteins to the liver, where they are hydroxylated by vitamin D-25-hydroxylase 
(CYP2R1) to produce 25-hydroxyvitamin D [25(OH)D], the primary circulating 
vitamin D metabolite used to assess an individual's vitamin D status. 25(OH)D is then 
transported to the kidney, where it is hydroxylated by 25(OH)-D-1α-hydroxylase 
(CYP27B1) and further hydroxylated to 1,25-dihydroxy vitamin D [1,25(OH)2D or 
calcitriol], the biologically active hormonal form of vitamin D10,11. In addition to its 
well-established roles in bone metabolism and immune function, emerging research 
suggests that vitamin D status may be inversely associated with the incidence of several 
diseases12-14. The vitamin D receptor has been found in cell types not involved in bone 
metabolism, revealing its impact on diverse physiological systems15,16. These findings 
have prompted an increase in the number of studies investigating the potential benefits 
of VDS, both alone and in combination with other therapies, for a variety of medical 
conditions. Regardless of age and geographic location, a substantial number of patients 
have been observed to have deficient levels of this essential micronutrient17. Evidence 
suggests that there is an association between vitamin D deficiency and LUTS, such as 

Efficacy and Safety of High-Dose Vitamin D Supplementation for Overactive Bladder Dry in Children: 
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those associated with OAB disorder18. This finding opens up new possibilities for the 
management of OAB through VDS.  Previous studies have reported that patients with 
OAB have lower serum vitamin D levels, and that VDS can serve as an alternative 
treatment option that reduces OAB-related symptoms and improves QoL in adults19-21. 
According to a meta-analysis and systematic review, high-dose VDS was linked with 
few supplement-related clinical adverse events in children between 0 to 6 years of age22. 
These findings suggest that VDS may be well-tolerated in young children within the 
dose range of 1200 to 10,000 IU/d. 
3. STUDY DESIGN.  
This study is conducted in the form of a prospective, observer-blind, parallel-group 
randomized controlled clinical trial. The study population will consist of children aged 
five years or older diagnosed with OAB-dry at the Children's Hospital of Chongqing 
Medical University, with serum vitamin D levels below 35ng/ml. We will exclude 
patients with other systemic organic diseases and those with poor compliance, thus 
representing a relatively ideal cohort. Participants will be randomly assigned to one of 
three intervention groups, including a group receiving a combination of high-dose 
vitamin D and SU, a group receiving a combination of solifenacin and SU, and a group 
receiving SU alone. 
This design allows for a thorough evaluation of the comparative efficacy and 
safety of various treatment regimens while minimizing sources of bias and confusion. 

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The randomized controlled design provides confidence that any observed differences 
between groups can be directly attributed to the experimental intervention, while the 
observer-blind method helps eliminate observer bias in assessment and outcome 
evaluation. 
The parallel-group design facilitates direct comparisons between the three 
intervention groups, generating insightful information about the relative efficacy of 
each regimen. The combination of high-dose vitamin D and SU represents a novel 
therapeutic approach. The solifenacin and SU combination group is included to 
investigate the effects of previously described anticholinergics agents on outcomes. The 
control group receiving SU alone serves as an important reference point, providing a 
baseline for comparisons with other intervention measures. 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS. 
4.1 Inclusion Criteria   
• 
Children older than 5 years of age with a diagnosis of OAB dry (do not 
experience incontinence yet suffer from symptoms of urgency, frequency, and nocturia) 
seen at the outpatient urology clinics (diagnosis follows the latest International 
Children's Continence Society recommendations). 
• Children with a serum vitamin D level of less than 35 ng/ml as indicated by 
the laboratory result. 

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• Written informed consent was obtained from the participants and their 
respective guardians. 
4.2 Exclusion Criteria  
• 
Those with a comorbidity of other urological abnormalities or serious diseases 
(e.g. hypospadias, cryptorchidism, posterior urethral valves, vesicoureteral reflux, 
neurogenic bladder, urological tumours, urinary stones, bladder and urethral injuries, 
etc.). 
• 
Those with a comorbidity of neurological disorders (e.g. epilepsy, spinal cord 
injury, spinal cord dysplasia, spinal cord embolism syndrome, multiple sclerosis, autism 
spectrum disorder, etc.). 
• 
Those with a comorbidity of severe heart disease, abnormal liver or kidney 
function, lung disease, skeletal deformities, severe gastrointestinal disease, or inherited 
metabolic disorders. 
• 
Those with a history of gastrointestinal surgery and urinary tract surgery. 
• 
Those with chronic constipation. 
• 
Those taking anticonvulsant and antiepileptic drugs, hormones, anti-
tuberculosis drugs. 
• 
Those have a previous history of hypercalcemia, hyperphosphatemia with 
renal rickets. 

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• 
Those have a history of hematuria and urinary tract infection within the last 1 
year. 
• 
Those have a history of allergy or allergic disease to vitamin D preparations. 
• 
Those Participate in other clinical studies at the time of consultation or during 
the follow-up of other clinical studies. 
• 
Any condition that could cause urinary symptoms or interfere with assessment 
of efficacy parameters. 
• 
Those unwilling to participate in this study. 
4.3 Study Enrollment Procedures  
Eligible participants will be selected from patients visiting the pediatric urology 
clinics at the Children's Hospital of Chongqing Medical University who have been 
diagnosed with OAB-dry and have serum vitamin D levels below 35ng/ml. The 
screening log will record reasons for both ineligibility and non-participation of eligible 
candidates. Prior to the commencement of intervention measures, interested patients 
will be required to provide informed consent. 
5. STUDY INTERVENTIONS  
5.1 Interventions, Administration, and Duration  
During the eight-week treatment period, the study was divided into three 
intervention groups, and each patient received follow-up care from an outpatient 

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physician every four weeks. Participants in each intervention group will be required to 
attend a 30-minute SU program per session. 
Children assigned to the VDS+SU group will receive high-dose VDS (800 IU, 
three times per day) in addition to the biweekly SU course. 
Children in the SOL+SU group will receive treatment with solifenacin succinate 
(5 mg once daily, with a maximum dose of 10 mg per day), in addition to the SU course. 
Participants in the SU group only attend regular SU meetings, which provide basic 
information and an explanation of the disease, guidance on behavioral changes and 
lifestyle advice, registration of urinary habits using a bladder diary, as well as support 
and encouragement from caregivers. 
5.2 Adherence Assessment  
Upon enrollment, all participants will be required to complete all relevant 
intervention treatments, as well as subsequent questionnaire surveys and efficacy 
assessments, without any interruption to the intervention treatment. 
6. STUDY PROCEDURES.  
6.1 Schedule of Evaluations  
Assessment 
Enrollment: Day1 
Run-in period (Day2-8) 
Week 4 (Day 33-
39) 
Week 8 (Day 61-67) 
Informed Consent Form 
√ 
 
 
 

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Demographics 
√ 
 
 
 
Medical History 
√ 
 
√ 
√ 
SU 
√ 
 
√ 
√ 
Bladder Diary 
 
√ 
√ 
√ 
Current Medications 
 
√ 
√ 
√ 
measurements of 
biochemistry. 
√ 
 
 
√ 
measurements of 
hematology, 
√ 
 
 
√ 
measurements of 
urinalysis. 
√ 
 
 
√ 
Adverse Events 
 
 
√ 
√ 
6.2 Description of Evaluations  
6.2.1 Screening Evaluation  
Eligible participants will be identified at the Outpatient Department of Urology, 
Children's Hospital of Chongqing Medical University. Patients will be further screened 
for eligibility by answering screening questions in a questionnaire (i.e., excluding 
exclusion criteria). 
6.2.1.1 Consent Procedure 
An informed consent form that describes the screening and study procedures will 
be used. The study coordinator will conduct the consent procedure in person. The 

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coordinator will describe the study to potential participants. The study coordinator and 
the principal investigator will regularly review the informed consent form for potential 
modifications. 
6.2.1.2 Screening 
Before the interventions begin, a screening assessment must be completed to 
determine eligibility. Medical records will be reviewed to identify patients who meet 
the relevant inclusion criteria and do not meet any exclusion criteria. These criteria will 
be confirmed at the time of enrollment through a questionnaire. 
6.2.2 Enrollment, Baseline, and/or Randomization  
6.2.2.1 Enrollment 
Participants who complete the eligibility screening, consent to participate, and 
provide an informed consent form for the study will be enrolled. Their contact 
information will be entered into the database. 
6.2.2.2 Baseline assessment 
All participants will have a 7-day run-in period during which children are asked to 
carefully record their OAB-dry symptoms. The purpose of this run-in period is to 
establish a baseline for evaluating the effect of the intervention measures investigated. 
6.2.2.3 Randomization 
After completing a comprehensive baseline assessment and meeting the eligibility 

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criteria, eligible participants will be randomized into one of three different intervention 
groups. To ensure the highest standard of allocation concealment, the randomization 
process of this clinical trial will be executed by a designed computer program developed 
by a project staff member who is not involved in the execution and statistical analysis 
of this study. The allocation will be securely hidden in sequentially numbered sealed 
envelopes, which will be entrusted to an inpatient doctor who is not involved in the trial. 
6.2.3 Blinding  
To minimize assessment bias and ensure the integrity of the study, we will 
implement rigorous measures to conceal group allocation and hypotheses from outcome 
assessors and statisticians. We will emphasize the importance of minimizing assessment 
bias to assessors and regularly review the blinding status to strictly maintain blinding. 
In addition, the data analyst will only be allowed to review coded data with participant 
names replaced by numbers. 
6.2.4 Follow-up Visits  
Patients will undergo regular follow-ups with an outpatient physician. Follow-up 
assessments will include measurements of urination frequency, urgency score, lower 
urinary tract symptom score, nocturia frequency, serum vitamin D levels, and other 
clinical laboratory parameters, such as hematology, biochemistry, and urinalysis. 
6.2.5 Completion/Final Evaluation  

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The effectiveness of various intervention measures for pediatric OAB-dry will be 
evaluated by comparing changes in the primary urinary frequency and urgency scores 
between the intervention groups. 
7. SAFETY ASSESSMENTS   
This study includes clinical interventions, and the primary focus of safety 
evaluation will be on assessing the adverse effects and exacerbation of clinical 
symptoms after oral administration of the drug. Patients will be encouraged to report 
any related complications or adverse events directly to us. 
7.1 Specification of Safety Parameters  
Participants were required to take solifenacin and high-dose VDS as part of the 
study. Anticholinergic side effects, including dry mouth, blurred vision, constipation, 
and nausea, among others, may occur due to solifenacin use. If any of these symptoms 
occur, the medication will be discontinued, and the participant will be removed from 
the study. Over-supplementation of vitamin D can lead to symptoms of vitamin D 
toxicity, including anorexia, nausea, diarrhea, constipation, irritability, and somnolence. 
Any occurrence of these adverse drug reactions or serum vitamin D levels exceeding 
100 ng/mL will be evaluated as unsafe. 
7.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters  
Enrolled participants will undergo follow-up visits every four weeks. These visits 

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will include a questionnaire and physical examination to assess any drug-related 
adverse effects, as well as a test of their serum vitamin D levels. In case any adverse 
effects arise, safety parameters will be promptly evaluated. 
7.3 Adverse Events and Serious Adverse Events  
The study may result in adverse events related to medication side effects of 
solifenacin and high-dose VDS. Adverse events and serious adverse events will be 
classified based on the severity and intensity of the side effects. 
7.4 Reporting Procedures  
In the event of any adverse event, investigators will be notified within 24 hours. 
7.5 Follow-up for Adverse Events  
In the event of an adverse event, patients will be advised to seek medical advice 
immediately. 
7.6 Safety Monitoring  
As mentioned above. 
8. INTERVENTION DISCONTINUATION  
If any drug-related adverse effects or worsening of OAB symptoms in children 
during the intervention period occur, intervention measures should be discontinued. 
Otherwise, the intervention measures will start eight weeks after enrollment and will 

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continue until the final data collection. At this point, study participants can withdraw 
their participation from this study. 
9. STATISTICAL CONSIDERATIONS   
9.1 General Design Issues   
Objective: The aim of this randomized controlled trial is to examine the 
effectiveness and safety of high-dose VDS plus SU for managing OAB-dry symptoms 
in pediatric patients with low vitamin D levels (<35ng/mL). 
Specific Aim 1: The main outcome is the difference in post-treatment 
improvement between children who receive high-dose VDS plus SU and those who 
receive solifenacin plus SU or SU monotherapy for OAB-dry symptoms. The study 
expects that high-dose VDS plus SU will lead to more improvement than SU 
monotherapy and solifenacin plus SU. Furthermore, SU monotherapy will result in less 
improvement than solifenacin plus SU.  
Specific Aim 2: The secondary outcome is the safety profile of high-dose VDS 
plus SU for OAB-dry symptoms in pediatric patients. The study anticipates that the 
safety profile of high-dose VDS plus SU will be similar to that of solifenacin plus SU 
or SU monotherapy at follow-up. 
The study design is an 8-week randomized controlled trial, and all treatments will 
be administered in a group setting. Pediatric patients with OAB-dry symptoms will 

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undergo 8 weekly sessions of high-dose VDS plus SU, solifenacin plus SU, or SU 
monotherapy. Independent assessors will evaluate the patients before the treatment, at 
mid-treatment (4-week follow-up), and at the 8-week follow-up to test the expectations. 
To account for attention, time, and group effects, all SU sessions will be administered 
in a group setting. 
9.2 Sample Size and Randomization   
Before we design the current trial, we did a preliminary study with the support of 
the Program for Youth Innovation in Future Medicine at Chongqing Medical University. 
This was to check if we could do the trial successfully and recruit enough participants. 
We recruited children who were between 5 and 18 years old and who had symptoms of 
urgency and urinated at least 9 times per day as recorded in a 7-day diary. A diary is a 
tool where participants record their symptoms and behaviors over a period of time. 
They chose to whether receive either high-dose VDS plus SU therapy for eight weeks, 
which is our new intervention. The Department of Pediatric Urology at the National 
Center for Clinical Medical Research (Chongqing) collected bladder diaries from 
participants before and after the treatment to evaluate how well the treatment worked. 
The main outcome was the change in how often they urinated, and other outcomes that 
we measured were how severe their urgency was, how often they woke up at night to 
urinate, and how bad their symptoms were using the PLUTS score. The PLUTS score 
is a tool that measures different aspects of lower urinary tract symptoms in children. 

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We also measured how much their symptoms bothered them and how their health-
related QoL was affected by their condition using the QoL score questionnaire. The 
QoL score is a tool that measures how satisfied participants are with their health and 
well-being. We also asked participants to rate how much they improved and how 
satisfied they were with the treatment using validated tools. The results of our 
preliminary study were positive and showed that our new intervention was promising. 
This encouraged us to continue with our main trial and test our intervention further. We 
created and finalized the study protocol, which is the document that describes the details 
and procedures of our study. We developed all data collection tools and forms, which 
are the tools and documents that we use to collect and record data from participants. 
We obtained IRB approvals at the National Clinical Research Center for Child Health 
and Disease (Chongqing, China), which are approvals from a committee that oversees 
the ethical aspects of our study and protects the rights and welfare of participants. We 
offered standard training to all coordinators and interventionists, who are the people 
who help us run the study and deliver the intervention to participants. Our preliminary 
data helped us to determine how many participants we needed for our main trial. 
The primary outcome in our study will be the change in median voiding frequency 
from enrollment to 4-week follow-up and 8-week follow-up. In our previous feasibility 
study, the mean number of voids per day was 16.0 (SD, 5.0) at enrollment. We used the 
power analysis program PASS 15.0 to estimate the sample size of this randomized 
controlled trial. A sample size of 87 participants per group was needed to detect a 

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difference of 1.5 voids per day between groups at the 0.05 level of significance, 
achieving more than 95% power, assuming an estimated SD of 5.0 after 8 weeks of 
treatment. We plan to recruit 97 participants per group, anticipating a 10% follow-up 
attrition, to ensure adequate power for the trial, for a total of about 300 participants. 
Our sample size estimations are supported by our previous trial. 
Independent assessors will be kept blind to the treatment allocation throughout the 
study. Patients will receive a reminder script emphasizing the importance of not 
revealing their treatment information before the assessment. Randomization codes will 
be created by the study statistician before recruiting the first participant in the trial. Data 
analysis will not start until after the study’s completion. 
9.3 Definition of Populations  
We will use different ways to summarize and analyze our data based on the type 
of outcome and variable that we are interested in.  
9.3.1 Intention-to-treat (ITT) analysis 
For outcomes that are continuous variables, which are numerical and can take any 
value within a range, we will use the ITT approach, which is a way of comparing the 
groups based on their original random assignment to a treatment, regardless of what 
treatment they actually received or completed. This helps to avoid bias from factors that 
may influence the results, such as dropout, which is when subjects leave the study 
before it ends, or crossover, which is when subjects switch to a different treatment than 

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they were assigned to. The ITT approach is also simpler than other ways of analyzing 
the data that need to consider whether the subjects followed the treatment as planned 
or not.  
9.3.2 Per protocol (PP) analysis set 
For outcomes that are categorical variables, which are non-numerical and can 
belong to one of several groups or categories, we will use the PP analysis set, which is 
a subset of subjects who followed the protocol without major deviations that could 
affect the outcomes. The protocol is the plan or procedure that we use to conduct the 
study. Deviations are when subjects do not follow the protocol as expected. For example, 
this includes patients who used other medications that were not allowed by the protocol 
or who did not follow the protocol properly. We will decide who to include or exclude 
in the PP analysis set before we lock the database, which is when we finalize the data 
after checking and cleaning them. 
9.3.3 Safety analysis set 
For safety analysis, which is when we assess the safety and side effects of the 
treatment, we will use the SS set, which is a subset of all patients who took at least one 
dose of the study drug and have safety records in the database. The database is where 
we store and manage our data electronically. We will only use measured values for this 
analysis, which are values that we actually observed and recorded for each subject. We 
will also do a sensitivity analysis using the PP analysis set, which is when we test how 

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robust our results are to different assumptions or scenarios. 
9.4 Interim Analyses and Stopping Rules   
During the study, we will not perform any interim analyses, which are analyses 
that are done before the end of the study to check the progress and results. We will only 
do interim analyses if the Institutional Review Board (IRB) requests them. If any SAEs 
occur during the study, we will report them to the IRB as quickly as we can follow their 
instructions. SAEs are events that are harmful or life-threatening to the subjects and 
that are unexpected, serious, and related to the intervention that we are testing. The IRB 
will have the responsibility to review the study and recommend whether to terminate it 
or not based on its assessment of the risks and benefits for the subjects. The IRB will 
do this if it determines that the subjects are exposed to more harm than good at any 
point during the study. 
9.5 Outcomes and data Analyses 
We will employ diverse measures to describe the characteristics of our data, 
depending on their nature. For numerical data that are continuous and can take any 
value within a range, we will use the mean (the arithmetic average of all values), the 
SD (a measure of how much the values deviate from the mean), the median (the central 
value when the data are sorted from the lowest to the highest), and the interquartile 
ranges (IQRs) (the range containing the middle 50% of data). For non-numerical data 
that are categorical and can belong to multiple groups or categories, we will use the 

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frequency (the number of occurrences for each category) and the percentile (the 
proportion of data that falls below a specific value or category). 
We will examine our data for any outliers or missing values that could influence 
our analysis. Outliers refer to values that differ significantly from the majority of the 
data and may indicate errors or exceptional cases, while missing values are data points 
that are unavailable or not recorded. Although we will employ effective data collection 
and management practices, missing values may still occur due to various factors. 
To estimate the missing values for continuous data, we will use multiple 
imputation. This approach replaces the missing values with plausible estimates based 
on the other available data. We will assume that the missing values are missing 
completely at random, meaning that their occurrence does not depend on any variable, 
including their value. We will also conduct a sensitivity analysis to determine if the 
missing values affect our results or conclusions.  
9.5.1 Primary Outcome  
The study aims to determine the primary outcomes of urinary frequency among 
three groups of participants. The frequency of urination will be recorded at three 
different points in time, i.e., when the participants enroll in the study, four weeks after 
starting the treatment, and eight weeks after starting the treatment. We will compare the 
frequency of urination between the groups at each time point, and assess changes in 
urination frequency from enrollment to four weeks after starting treatment. To record 

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urinary frequency, we will use a bladder diary, and these outcomes will be considered 
continuous variables, with any positive integer value within a specified range. 
To analyze the data, we will use the intention-to-treat approach to avoid bias from 
factors such as dropout or crossover. We will also handle missing data before analysis. 
Statistical tests will be applied to compare the groups based on data distribution and 
variance, which affects the reliability of results. For normally distributed data with 
homogeneous variance, we will use ANOVA, followed by post-hoc comparisons and 
Bonferroni correction to reduce Type I errors. We will report data changes using mean 
and SD and differences between groups using point estimation and 95% confidence 
intervals (95%CI). 
For non-normally distributed data with heterogeneous variance, we will use the 
Kruskal-Wallis test to compare groups. Post-hoc comparisons between groups will be 
done using the Wilcoxon rank sum test, and p-values will be adjusted by Bonferroni 
correction. Data changes will be reported using median and IQRs, and differences 
between groups using the Hodges-Lehmann (HL) estimate of location shift and 95% 
confidence intervals (95%CI). P-values will also be adjusted for multiple comparisons 
to avoid false positives, and a two-tailed P-value less than .05 will be considered 
statistically significant. 
9.5.2 Secondary Outcomes 
We will measure and compare secondary outcomes that are important for our study, 

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even though they are not the main outcomes. These outcomes comprise different types 
of variables, including continuous variables that are numerical and can take any value 
within a range. Some of the secondary outcomes that we will measure are the average 
change in urgency severity, the maximum change in urgency severity, the frequency of 
nocturia, the impact on the participants' QoL, and the severity of LUTS using the 
PLUTS score. We will measure these outcomes from the time participants enroll in the 
study to 4 and 8 weeks after they start the treatment. We will compare these outcomes 
and their changes over time between the groups. 
To compare the groups, we will use various statistical tests based on how the data 
are distributed and how much they vary between the groups. The data's distribution 
describes how they are shaped and spread out and determines the statistical tests we can 
use. The variance of the data shows how much the values differ from each other within 
and between the groups, affecting the reliability of the results. 
For normally distributed data with homogeneous variance, we will use the 
ANOVA test, which compares three or more groups with continuous data to identify 
significant differences between them. We will report the data and their change using 
mean and SD, which show the average and variability of the data, respectively. 
Additionally, we will perform post-hoc comparisons between groups to see which 
specific groups are different from each other. We will report these comparisons using 
point estimation and 95% confidence intervals (95%CI), which show how precise our 

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estimates are and how likely they are to include the true value. An adjusted P value will 
be reported for each comparison to avoid false positives. 
For data that are not normally distributed or have heterogeneous variance, we will 
use the Kruskal-Wallis test to compare the groups. The Kruskal-Wallis test is suitable 
for comparing three or more groups with continuous data that do not meet the 
assumptions of ANOVA. We will report the data and their change using median and 
IQRs, which show the middle and range of the data. Additionally, we will perform post-
hoc comparisons between groups using the Wilcoxon rank-sum test, which can compare 
two groups with continuous data that do not meet ANOVA assumptions. We will report 
these comparisons using the HL estimate of location shift and 95% confidence intervals, 
which show how much one group differs from another group in terms of location or 
central tendency. We will also report an adjusted P value for each comparison. 
We will assess and compare how participants perceive their improvement from 
enrollment in the study to 4 and 8 weeks after treatment initiation. This subjective 
outcome reflects how participants feel about their condition and treatment, which we 
will measure using a rating scale with categories such as much better, better, about the 
same, or worse. Since this is non-numerical, ordered categorical data, we will use the 
PP analysis set to analyze the subset of subjects who adhered to the protocol without 
major deviations. We will apply the Kruskal-Wallis test to compare groups based on 
their ratings of improvement at different time points, reporting the data using frequency 

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and percentile. We will use a two-tailed P-value to determine statistical significance, 
setting a cutoff of less than .05, unless specified otherwise. 
Additionally, we will record and compare participant satisfaction with the current 
treatment and their willingness to receive another therapy. This dichotomous outcome 
measures whether participants answered yes or no to whether they would like to receive 
another therapy. We will use the PP analysis set and the chi-square test to compare the 
groups based on their responses at different time points. We will report the data using 
frequency and percentile, and consider a P-value of less than .05 to be statistically 
significant, unless specified otherwise. 
9.5.3 Safety analysis  
The safety analysis will be performed using the Safety Analysis Set, which will 
assess treatment-emergent adverse events (TEAEs). Detailed recordings of all severe 
adverse events and TEAEs leading to discontinuation from the study will be included. 
Changes in clinical laboratory parameters and vital signs at each scheduled time point 
from baseline will be summarized according to treatment groups. 
10. DATA COLLECTION AND QUALITY ASSURANCE   
10.1 Data Collection Forms  
In our study, we intend to measure and compare different outcomes using various 
tools, such as questionnaires and rating scales. Participants will be required to answer 

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questions or rate their symptoms or behaviors on a scale. To minimize bias and increase 
the validity of the results, clinicians and independent evaluators will be trained to 
administer the questionnaires and scales without knowing which treatment group each 
participant belongs to. We will take steps to ensure that our data is accurate and that we 
adhere to the protocol. In cases where children can report their symptoms well, we will 
consider both what the child and parent say equally, and discrepancies between the two 
reports will be investigated further. 
We will utilize QR codes to enable participants to fill out self-report forms, which 
can be scanned by a smartphone or tablet and linked to a website. Program alerts will 
be used to remind participants to answer all questions and enter valid values. We will 
maintain confidentiality and compliance throughout the study, labeling data by subject 
number, visit number, and date of visit only in our database. Participants will be given 
a unique ID number that only we can link to their names. To ensure data security, we 
will encrypt and password protect all electronic data transfers. Hard copies of personal 
health information and consent forms, as well as study measures on paper, will be kept 
in locked drawers by another researcher. 
The research team will conduct regular reviews to evaluate the quality and 
completeness of data collected during the study, including patient intake and retention 
progress, patient compliance with visits, evaluations, and treatments as per the protocol, 
any adverse events or safety concerns, and the accuracy and completeness of key data 

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elements required to characterize patients. These reports will assist the research group 
in determining the effectiveness of data capture and processing methods to facilitate 
scientifically sound analyses. 
10.2 Data Management  
The biostatisticians will manage the study database, while the principal 
investigators (Xing Liu) will oversee the researchers and data management staff to 
ensure the quality and execution of the study. X Wang, MD, will supervise the data 
management and quality. The collected data will include various assessments, such as 
screening data, clinician- and patient-rated assessments, fidelity, visit adherence, and 
safety data, as well as interrater reliability and certification data. Weekly reports will 
track enrollment, completion, attrition, subject progress, and critical assessments. 
Baseline characteristics, protocol adherence, and other issues will be monitored using 
additional reports as necessary. 
Data will be collected directly by patients and study staff through a QR code, 
which links to a website. The data will be exported to a relational database in Microsoft 
software for systematic querying and checking. Paper-based data will be entered by 2 
independent staff members to prevent errors or missing data and verified by another 
staff member at the end of the study. 
Monthly reports will monitor enrollment, completion, attrition, subject progress, 
and critical assessments. Additional reports will monitor baseline characteristics, 

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protocol adherence, and other issues. Data will be de-identified using subject number, 
visit number, and date of visit to comply with local privacy requirements. Electronic 
data will be encrypted and password-protected, with only ID numbers being used to 
identify subjects. De-identified data will be transmitted for data analysis. Consent forms 
and hard copy protected health information will be kept in locked cabinets in a secure 
office. 
10.3 Quality Assurance  
10.3.1 Training   
The study will provide training to participants on how to use bladder diaries and 
rating scales. The individuals providing the training, called SU trainers, will be unaware 
of the treatment assignment. The diagnostic and efficacy evaluations will be reliable 
and valid, ensuring that the results of the study are trustworthy. To ensure that all raters, 
including children and parents, are providing accurate ratings, they will receive specific 
training on the rating scales. The training will focus on issues such as overestimation, 
underestimation, and recall period. The SU trainers will also administer SU sessions. 
The reliability and integrity of these sessions will be established and maintained 
through specific training, certification, and weekly meetings. All SU trainers will be 
experienced clinicians who have met the same criteria for teaching behavioral therapy. 
Any new SU trainers will undergo training and have their sessions reviewed by an SU 
expert for agreement. Weekly meetings will also help reduce the potential for training 

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bias. By implementing these procedures, the study aims to ensure that participants 
understand and effectively use behavioral therapy. 
10.3.2 Protocol Deviations  
Any protocol deviations will be recorded in the protocol deviation log and 
reviewed with the study PI at weekly meetings. 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 IRB Review  
This protocol and the informed consent document have been reviewed and 
approved by the institutional review board of Children's Hospital of Chongqing 
Medical University. This Clinical Trial will be conducted in compliance with national 
laws and regulations, as well as any applicable guidelines.  
11.2 Informed Consent Forms  
In accordance with local regulations, participants in the study will be required to 
provide informed consent. For children over the age of eight, both the child and legal 
guardian must sign the informed consent form, whereas for children under eight years 
of age, only the legal guardian needs to sign. 
To ensure that each participant has a full understanding of the study's nature, 
potential risks and benefits, and purpose, the study team will provide both oral and 
written information. Participants will be informed that they have the right to withdraw 

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from the study at any time and will be given sufficient time to consider the information 
provided and ask questions before providing their signed and dated informed consent. 
The original, signed informed consent forms will be stored in the Investigator's Study 
File, and a copy will be given to the subject. The informed consent form will also 
describe any incentives for study participation and any provisions for subjects who may 
experience harm as a result of their participation. 
Ensuring informed consent is critical to upholding ethical standards in research, 
and these procedures will help ensure that each participant fully understands the study 
and has given informed consent before participating. 
11.3 Participant Confidentiality  
To protect the confidentiality of participants, any data, forms, reports, or other 
records that are taken away from the research site will be identified only by a participant 
identification number (PID). These records will be stored in a secure and locked file 
cabinet, and computer programs will also use only PIDs for data entry and networking. 
The information will not be disclosed without written permission from the participant, 
except for monitoring by the IRB. 
11.4 Study Discontinuation 
The study may be discontinued at any time by the IRB or other government 
agencies as part of their duties to ensure that research participants are protected. 
11.5 Monitor 

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The monitoring plan should be prepared by the monitor before the start of the study, 
and monitoring should be performed in accordance with this plan during the study. The 
IRB is responsible for monitoring the proper execution of the study and ensuring the 
consistency and availability of data through a management and observation plan. The 
primary role of the monitoring team is to assist investigators in maintaining high quality 
standards in ethics, scientific methods, techniques, and laws. Additionally, the 
monitoring team must ensure that the study is conducted in compliance with the Clinical 
Trial Protocol, Chinese GCP, and SOP. The monitoring team will inspect the following 
during the study's monitoring: subject recruitment and follow-up, SAE records and 
reports, the distribution of investigational drugs, protocol compliance for, and data 
quality. 
12 AUDITS 
The IRB auditor will conduct a comprehensive audit of all clinical study-related 
activities and documents to evaluate compliance with the protocol, standard operating 
procedures, and relevant regulations. The accuracy, completeness, and timeliness of the 
recorded data will also be evaluated. To ensure impartiality, the audits will be conducted 
by personnel or group who are not involved in the clinical study. 
14. REFERENCES   
1. Franco I. Overactive bladder in children. Nat Rev Urol. 2016;13(9):520-532. 
2. Robinson D, Cardozo L. Managing overactive bladder. Climacteric. 

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 A Randomized Clinical Trial (Edition Number:3) 
31 
 
2019;22(3):250-256. 
3. Irwin DE, Milsom I, Kopp Z, Abrams P, Artibani W, Herschorn S. Prevalence, 
severity, and symptom bother of lower urinary tract symptoms among men in the EPIC 
study: impact of overactive bladder. Eur Urol. 2009;56(1):14-20. 
4. Peyronnet B, Mironska E, Chapple C, et al. A Comprehensive Review of 
Overactive Bladder Pathophysiology: On the Way to Tailored Treatment. Eur Urol. 
2019;75(6):988-1000. 
5. Nieuwhof-Leppink AJ, Hussong J, Chase J, et al. Definitions, indications and 
practice of urotherapy in children and adolescents: - A standardization document of the 
International Children's Continence Society (ICCS). J Pediatr Urol. 2021;17(2):172-181. 
6. Newgreen D, Bosman B, Hollestein-Havelaar A, et al. Solifenacin in Children and 
Adolescents with Overactive Bladder: Results of a Phase 3 Randomised Clinical Trial. Eur 
Urol. 2017;71(3):483-490. 
7. Newgreen D, Bosman B, Hollestein-Havelaar A, et al. Long-Term Safety and 
Efficacy of Solifenacin in Children and Adolescents with Overactive Bladder. J Urol. 
2017;198(4):928-936. 
8. Borel P, Caillaud D, Cano NJ. Vitamin D bioavailability: state of the art. Crit Rev 
Food Sci Nutr. 2015;55(9):1193-1205. 
9. Bikle DD. Vitamin D and the skin: Physiology and pathophysiology. Rev Endocr 
Metab Disord. 2012;13(1):3-19. 
10. Bikle D, Christakos S. New aspects of vitamin D metabolism and action - 
addressing the skin as source and target. Nat Rev Endocrinol. 2020;16(4):234-252. 

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11. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: 
Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects. Physiol Rev. 
2016;96(1):365-408. 
12. Saggese G, Vierucci F, Boot AM, et al. Vitamin D in childhood and adolescence: 
an expert position statement. Eur J Pediatr. 2015;174(5):565-576. 
13. Taylor SN. Vitamin D in Toddlers, Preschool Children, and Adolescents. Ann 
Nutr Metab. 2020;76 Suppl 2:30-41. 
14. Föcker M, Antel J, Ring S, et al. Vitamin D and mental health in children and 
adolescents. Eur Child Adolesc Psychiatry. 2017;26(9):1043-1066. 
15. Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. 
Nutrients. 2013;5(7):2502-2521. 
16. Gnagnarella P, Raimondi S, Aristarco V, et al. Vitamin D Receptor 
Polymorphisms and Cancer. Adv Exp Med Biol. 2020;1268:53-114. 
17. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and 
prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin 
Endocrinol Metab. 2011;96(7):1911-1930. 
18. Özçift B, Micoogullari U. The effect of vitamin D deficiency in children with 
overactive bladder related urinary incontinence. Int Braz J Urol. 2022;48(2):316-325. 
19. Markland AD, Tangpricha V, Mark Beasley T, et al. Comparing Vitamin D 
Supplementation Versus Placebo for Urgency Urinary Incontinence: A Pilot Study. J Am 
Geriatr Soc. 2019;67(3):570-575. 
20. Markland AD, Vaughan CP, Huang AJ, et al. Effect of Vitamin D 

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Supplementation on Overactive Bladder and Urinary Incontinence Symptoms in Older Men: 
Ancillary Findings From a Randomized Trial. J Urol. 2023;209(1):243-252. 
21. Yoo S, Oh S, Kim HS, et al. Impact of serum 25-OH vitamin D level on lower 
urinary tract symptoms in men: a step towards reducing overactive bladder. BJU Int. 
2018;122(4):667-672. 
22. Brustad N, Yousef S, Stokholm J, Bønnelykke K, Bisgaard H, Chawes BL. Safety 
of High-Dose Vitamin D Supplementation Among Children Aged 0 to 6 Years: A 
Systematic Review and Meta-analysis. JAMA Netw Open. 2022;5(4):e227410. 
 
 
 

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15. SUPPLEMENTS  
Pediatric Lower Urinary Tract Symptom Score (PLUTS score) 
ID：            
1.Does your child wet during the 
day? 
□ NO 
□Sometimes 
□1-2times/day 
□ Always 
0 
1 
3 
5 
2. How wet is your child during 
the day? 
□Damp 
underwear 
□ Damp pants 
only 
□ Pants soaking 
wet 
1 
3 
5 
3. Does your child wet during the 
night? 
□ No 
□ 1–2 Nights/ 
week 
□ 3–5 Nights/ 
week 
□6–7 Nights/ 
week 
0 
1 
3 
5 
4. How wet is your child during the 
night? 
□ Damp bed sheet only 
□ Bed sheets soaking wet 
1 
4 
5. How many times does your child 
void? 
□ Less than7/day 
□ 7 or more than 7/day 
0 
1 
6. My child strains during voiding. 
□ No 
□ Yes 
0 
3 
7. My child feels pain during 
voiding 
□ No 
□ Yes 
0 
1 
8. My child voids intermittently 
□ No 
□ Yes 
0 
2 
9. My child needs to go back 
voiding soon after finishes his/her 
pee. 
□ No 
□ Yes 
0 
2 
10. My child has a sudden feeling of 
having to urinate immediately 
□ No 
□ Yes 
0 
1 
11. My child holds by crossing 
his/her legs. 
□ No 
□ Yes 
0 
2 
12. My child wets on the way to the 
toilet  
□ No 
□ Yes 
0 
2 
13. My child misses his/her bowel 
movement every day. 
□ No 
□ Yes 
2 
0 
14. If your child experiences 
symptoms mentioned above, does it 
affect his/ her family, social or 
school life? 
□ Not at all 
□ Sometimes 
□ Seriously affects 
0 
1 
5 
Total score：                       Date：