A Cohort Study on Treating Primary Nocturnal Enuresis by Regulating Central-Peripheral Circadian Rhythm

Not Applicable

Not yet recruiting

• Conditions: Primary Nocturnal Enuresis

• Registration Number: NCT07003126
• Lead Sponsor: Shanghai Children's Medical Center

Brief Summary

Primary nocturnal enuresis (PNE), a prevalent pediatric disorder, suffers from therapeutic limitations characterized by low efficacy and high relapse rates. Targeting its core pathophysiology could significantly improve treatment outcomes. Growing evidence implicates circadian dysregulation in PNE pathogenesis. Our preliminary fMRI cohort identified abnormal functional connectivity between the suprachiasmatic nucleus (SCN, the central circadian pacemaker) and superior temporal gyrus in PNE patients, with clinical data confirming circadian realignment correlates with symptom remission. Small-scale pilot studies and clinical observations indicate that modulating central and peripheral circadian rhythms significantly alleviates PNE symptoms. This study will establish a circadian-focused PNE cohort to quantify therapeutic efficacy and elucidate underlying mechanisms, ultimately driving the development of mechanism-based therapies for PNE.

Detailed Description

The intervention training will last for 6 months. Researchers will compare the therapeutic efficacy of the "Circadian Rhythm Intervention Combined with Bladder Training Group (treatment group)" and the "Bladder Training (basic treatment for enuresis) Only Group (control group)" for PNE.

Participants will be assigned to either the "Circadian Rhythm Intervention Combined with Bladder Training Group (treatment group)" or "Bladder Training (basic treatment for enuresis) Only Group (control group)" through stratified block randomization matching participants by sex (male/female), age (in years), and enuresis frequency. Within each stratified subgroup, block randomization with a 1:1 allocation ratio will be implemented using computer-generated random sequences, ensuring balanced demographic distribution between the two intervention arms while maintaining concealment of allocation sequence.

In the "Circadian Rhythm Intervention Combined with Bladder Training Group (treatment group)", participants will receive a 6-month behavioral therapy including both bladder training and circadian rhythm intervention. Bladder training combined with circadian rhythm interventions involves sleep hygiene optimization, individualized chronotype alignment, morning bright light therapy and bladder training component. The bladder training component (basic treatment for enuresis) includes fluid intake modification, micturition desire-relaxation training, and sphincter control training. Clinical symptom severity and key pathophysiological parameters will be evaluated at baseline and at 6 months post-intervention.

In the "Bladder Training Only Group (control group)", participants will receive a 6-month behavioral therapy including only bladder training. The bladder training component (basic treatment for enuresis) includes fluid intake modification, micturition desire-relaxation training, and sphincter control training. Clinical symptom severity and key pathophysiological parameters will be evaluated at baseline and 6 months post-intervention.

The investigators will compare changes in enuresis improvement rate, resting-state functional magnetic resonance imaging data, sleep physiological parameters, salivary melatonin levels, diurnal and nocturnal urine volume, standardized bladder capacity, and grade scoring of the micturition desire-awakening function before and after the intervention.

Study Timeline

• Status Verified: 2025-05
• Study First Submitted: 2025-05-25
• Study First Submitted QC: 2025-06-03
• Last Update Submitted: 2025-06-03
• Study First Posted: 2025-06-04
• Last Update Posted: 2025-06-04
• Study Start: 2025-07-01
• Primary Completion: 2027-12-30
• Study Completion: 2028-06-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

1. Diagnosis according to the ICCS criteria:

   At least one episode of involuntary nighttime urination per month for more than 3 months.

   No abnormalities in routine urinalysis. No period of bedwetting-free days lasting more than 6 months, except for organic diseases.

2. Age: 5 to 15 years (inclusive), regardless of gender.

3. Right-handedness (as assessed by the Annett Hand Preference Questionnaire)

Exclusion Criteria

1. Secondary nocturnal enuresis;
2. History of head trauma, neurological disorders, psychosurgery, or major physical conditions (including autism spectrum disorder, epilepsy, cerebral palsy);
3. Contraindications to fMRI.
4. Note: Mild comorbidities commonly associated with primary nocturnal enuresis (e.g., ADHD) are permitted but must be included as covariates in statistical analyses.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Enuresis Improvement Rate	From enrollment to the end of treatment at 6 months	The enuresis improvement rate is the sum of the complete and partial response rates.; No response: \<50% reduction. Partial response: 50 to 99% reduction. Complete response: 100% reduction.

Secondary Outcome Measures

Name	Time	Method
Resting-State Functional Magnetic Resonance Imaging (fMRI) Data	From enrollment to the end of treatment at 6 months	Resting-state fMRI data will be acquired to characterize brain functional networks, with a focus on analyzing functional connectivity between the suprachiasmatic nucleus and superior temporal gyrus.
Diurnal and Nocturnal Urine Volume	From enrollment to the end of treatment at 6 months	Participants will complete at least one 24-hour fluid intake and voiding diary per week, including diurnal and nocturnal urine volume recorded pre-treatment, during treatment, and post-treatment.; Daytime voiding will be measured using graduated plastic cylinders for each urination. Nocturnal voiding will be recorded by wearing pre-weighed diapers (with urine volume calculated by weighing the diapers the next day) or through timed voiding upon waking during the night.; The average total diurnal and nocturnal urine volume during each recorded period will be calculated as the participant's diurnal and nocturnal urine volume at different time points.
Heart Rate Variability	From enrollment to the end of treatment at 6 months	Continuous measurement of beat-to-beat intervals assessed via research-grade wearable actigraphy, using artificial intelligence-driven chronobiological analytics to extract features.; Unit of Measure: Milliseconds
Polysomnography-Validated Sleep Metrics	From enrollment to the end of treatment at 6 months	Sleep efficiency validated against polysomnography benchmarks and derived from wearable actigraphy data streams.; Unit of Measure: Percent (%)
Grade scoring of the micturition desire-awakening function	From enrollment to the end of treatment at 6 months	The grade scoring of the micturition desire-awakening function based on the average awakening ability each night. The grade scoring of the micturition desire-awakening function is as follows: Grade 5: Remains asleep most of the time after urination. Grade 4: Only awakens after completely wetting the bed. Grade 3: Awakens only after urinating a significant amount and then goes to the toilet to void the remaining urine.; Grade 2: Awakens after urinating a small amount and then goes to the toilet to void the remaining urine.; Grade 1: Awakened by the urge to urinate, without wetting the bed.
Standardized Bladder Capacity	From enrollment to the end of treatment at 6 months	Standardized bladder capacity = bladder capacity/body surface area. Compare the standardized mean bladder capacity as well as the maximum and minimum daytime/nighttime bladder capacity changes from baseline to 6 months.; The term mean daytime bladder capacity refers to the average volume of voided urine measured on the frequency volume chart throughout a 24-hour cycle.; The term maximum/minimum daytime bladder capacity refers to the largest/smallest volume of voided urine measured on the frequency volume chart during the day. It excludes the first morning void.; The term maximum/minimum nighttime bladder capacity refers to the largest/smallest volume of voided urine measured on the frequency volume chart during the night. It includes the first morning void.
Salivary Melatonin Levels	From enrollment to the end of treatment at 6 months	Saliva samples (2 mL each) will be collected from children with PNE at 4-hour intervals starting at 09:00, yielding seven timepoints (09:00, 13:00, 17:00, 21:00, 01:00, 05:00, and 09:00 the following day) within a ±1-hour window. Collections at 21:00, 01:00, and 05:00 will be performed under dim-light conditions (ambient illumination \<30 lux).; Salivary melatonin concentrations will be quantified using liquid chromatography-tandem mass spectrometry-a rapid, sensitive, and reliable method validated for low-abundance hormone detection in saliva.

Trial Locations

Locations (1)

Shanghai children's medical center; 🇨🇳 Shanghai, Shanghai, China