EA for BPS: An RCT and Study for Central Mechanism

Study Overview
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Brief Summary
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This is a randomized controlled and assessor-blinded design trial to evaluate the efficacy and safety of acupuncture for bladder pain syndrome(BPS). All eligible participants will be randomly assigned to the medication group(n=21), EA group(n=42) and SA group(n=21) in a 1:2:1 allocation ratio. Participants will receive 4-week treatments phase followed by a 4-week follow-up phase. Outcomes will be assessed at baseline, during the treatment and at the end of the follow-up. Outcome assessors, data managers and statisticians will be blinded to the group allocation, while acupuncturists and participants will not be blinded for obvious reasons. Besides, fMRI will be used to collect spontaneous electrical activity of the brain of patients. In this trial, the investigators assume that electroacupuncture for BPS, compared to amitriptyline, is instrumental in improving symptoms such as pain, frequent micturition and emotional disorder.

Detailed Description
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Participants will be primarily recruited from gynecology, urology and acupuncture departments during outpatient service. All patients will be randomly assigned to either the medication group, EA group or SA group via random number table. SAS 9.3 software will be adopted to generate random numbers. The independent clinical research assistant will be responsible for generating random numbers and making random allocation cards, each with its group allocation information and sealed into an opaque envelope, which will not be open until the first treatment. According to the order of enrollment, eligible participants will be randomly assigned into the medication, EA or SA group at 1:2:1 ratio under the allocation in the envelope. Due to the characteristics of acupuncture, acupuncture manipulators cannot be blinded. Nevertheless, to avoid the subjective bias of researchers and subjects, outcome assessment and statistical analysis will be performed by different researchers blinded to the allocation information. Patients are informed that they will receive one of two effective acupuncture interventions after enrollment, and during the treatment, patients in EA or SA groups will be in separate rooms to avoid communication. Outcome assessors and statisticians will be blind to the group allocations. The participant's allocated intervention will not be revealed until the statistical analysis reports are completed. Participants in the medication group will be merely treated with oral administration of amitriptyline capsule. The dosage of amitriptyline is 25 mg bid, for 4 weeks. Any changes in the medications of individual participants will be recorded on diary cards. In EA group, acupuncture treatment is carried out by acupuncturists who have been well trained. Acupuncture will be performed with disposable and sterile needles in the specification of 0.25 ×40 mm(diameter: 0.25 mm; Suzhou Medical Products Factory Co., Ltd, China). Patients are asked to lie in a prone position with whole body relaxed. Both the skin around the selected acupoints and the hand of acupuncturists are routinely disinfected, after insertion, manipulations of twirling, lifting and uniform reinforcing reducing manipulation will be performed on all needles to elicit 'deqi'. The compositional sensation of 'deqi' involves with numbness, soreness, distention, aching and heaviness, which are believed to be an essential component for acupuncture efficacy. Electroacupuncture procedures will be performed with electronic instruments (Hans-100A, Nanjing Jisheng Medical TechnologyCo., Ltd, China). Two paired of acupoints (i.e., two Shenshu(BL23) and two Ciliao(BL32), respectively) are connected to the EA apparatus. Alternating-frequency mode is selected and frequency is 2/100 Hz. EA intensity is determined in accordance with patients' endurance. EA will last for 30 min for each treatment. Patients will receive a total number of 12 EA sessions, with the frequency of 3 sessions per week for 4 weeks. In SA group, Acupuncture will be conducted by well-trained acupuncturists and performed with disposable and sterile needles in the specification of 0.25×40 mm (diameter: 0.25 mm; Suzhou Medical Products Factory Co., Ltd, China). Patients are asked to lie in a prone position with whole body relaxed. Both the skin around the selected acupoint and the hand of acupuncturists are routinely disinfected. The needles are subcutaneously inserted to non-meridian and non-acupoints regions. SA procedures will be performed with electronic instruments (Hans-100A, Nanjing Jisheng Medical Technology Co., Ltd, China). Two paired of points are connected to the electronic instruments. Alternating-frequency mode is selected and the frequency is 2/100 Hz. Different from the EA group, the apparatus will run without electricity in the SA group. The procedure will last for 30 min. Patients will receive a total number of 12 SA sessions, with the frequency of 3 sessions per week for 4 weeks. Outcomes, such as Visual analog scale, O'Leary-Sant questionnaire, 24-hour voiding diary, Hamilton Anxiety Scale and Hamilton Depression Scale, will be assessed at baseline, during the treatment and at the end of the follow-up. Outcome assessors, data managers and statisticians will be blinded to the group allocation, while acupuncturists and participants will not be blinded for obvious reasons. Besides, fMRI will be used to collect spontaneous electrical activity of the brain of patients, and the changes of spontaneous electrical activity of specific brain regions, resting brain functional connectivity and information interaction of multifunctional areas will be analyzed.

Official Title
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Electroacupuncture for Bladder Pain Syndrome: An Randomized Controlled Trial and Study for Central Mechanism

Conditions
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Bladder Pain Syndrome

Intervention / Treatment
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* Procedure: electroacupuncture
* Drug: Amitriptyline
* Procedure: sham electroacupuncture


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 ≤ age ≤70 years, male or female; Must fulfill the first and the second diagnostic criteria; 30 mm≤ VAS score ≤80mm; Participants can fully understand the study protocol and a written informed consent is signed. Exclusion Criteria: Patients with previous bladder stones or other space-occupying lesions; Previous positive urine culture or significant abnormal urine routine; Significant organic lesions of genitourinary system and pelvic organs; Patients suffer from severe primary diseases such as cardiovascular, cerebrovascular, respiratory, liver and kidney, or patients cannot receive EA treatment due to any reasons; People with heart stents and other metallic substances in their bodies; Women who are pregnant, planning to become pregnant, breast-feeding or allergic to study drugs; Patients have participated in other clinical trials within the last 3 months.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: medication group<br>Participants in the medication group will be merely treated with oral administration of amitriptyline capsule. The dosage of amitriptyline is 25mg bid, for 4 weeks. Any changes in the medications of participants will be recorded on diary cards. | Drug: Amitriptyline<br>* Participants in the medication group will be merely treated with oral administration of amitriptyline capsule. The dosage of amitriptyline is 25mg bid, for 4 weeks. Any changes in the medications of individual participants will be recorded on diary cards.<br>|
| Experimental: EA group<br>Patients allocated to this group will receive treatment with electroacupuncture. The location of acupoints will be determined based on the National Standard Nomenclature and Location of Acupoints. Patients will receive a total number of 12 EA sessions, with the frequency of 3 sessions per week for 4 weeks. | Procedure: electroacupuncture<br>* The prespecified acupoints applied here will include bilateral Sanyinjiao(SP6), Shenshu(BL23), Ciliao(BL32), Zhongliao(BL33), Zhibian(BL54) . Acupuncture treatment is carried out by acupuncturists who have been well trained. Acupuncture will be performed with disposable and sterile needles in the specification of 0.25 ×40 mm(diameter: 0.25mm; Suzhou Medical Products Factory Co., Ltd, China). Electroacupuncture procedures will be performed with electronic instruments (Hans-100A, Nanjing Jisheng Medical TechnologyCo., Ltd, China). Two paired of acupoints (i.e., two Shenshu(BL23) and two Ciliao(BL32), respectively) are connected to the EA apparatus. Alternating-frequency mode is selected and frequency is 2/100 Hz. EA intensity is determined in accordance with patients' endurance. EA will last for 30 min for each treatment. Patients will receive a total number of 12 EA sessions, with the frequency of 3 sessions per week for 4 weeks.<br>|
| Sham Comparator: SA group<br>Patients allocated to this group will receive acupuncture in non-meridian and non-acupoints regions. The needles are shallowly inserted to the subcutaneous area, and acupoints are connected to the EA apparatus without electricity. The frequency, intensity and duration of treatment will be the same as the EA group. | Procedure: sham electroacupuncture<br>* In the trunk region, the points are 5 cm away from respective acupoints. In the lower limb region, the point is 3 cm away from Sanyinjiao(SP6). All points will only receive shallow insertion. Acupuncture will be performed with disposable and sterile needles in the specification of 0.25 ×40 mm(diameter: 0.25mm; Suzhou Medical Products Factory Co., Ltd, China).The needles are shallowly inserted to the subcutaneous area, and acupoints are connected to the EA apparatus without electricity. The frequency, intensity and duration of treatment will be the same as the electric needle group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in VAS score for pain intensity from baseline to 2 weeks, 4 weeks and 8 weeks after randomization. | Pain intensity will be measured using a 0-100 VAS, with 0 indicating no pain and 100 indicating maximal pain. | at baseline(week 0)、week 2、week 4 and week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in O'Leary-Sant questionnaire from baseline to 4 weeks, 8 weeks after randomization. | O'Leary-Sant questionnaire include interstitial cystitis Inflammation Index (ICSI) and interstitial Cystitis Problems Index (ICPI). Both ICSI and ICPI contain 4 questions. ICSI mainly assesses the severity of symptoms and every item estimation score ranges between 0 and 5. The total score ranges from 0 to 20 and higher scores indicate more severe symptoms. ICPI evaluates the degree of distress to the patient and every item estimation score ranges from 0 to 4. The total score ranges from 0 to 16; higher score represent, the more serious the distress. | at baseline(week 0)、week 4 and week 8 | 
| 24-hour voiding diary | The frequency of urination and the special feeling during the urination will be carefully recorded every day. | every day during the 4-week treatment phase | 
| Changes in Hamilton Anxiety Scale from baseline to 4 weeks, 8 weeks after randomization. | Hamilton Anxiety Scale is represented by 14 items. Every item estimation score ranges between 0 and 4. The total score ranges from 0 to 56. Higher the score, severe the situation. In this scale, score 7-14 indicates mild severity, 15-21 represents mild to moderate severity, 22-28 represents moderate severity, and >28 indicates severe condition. | at baseline(week 0)、week 4 and week 8 | 
| Changes in Hamilton Depression Scale from baseline to 4 weeks, 8 weeks after randomization. | Hamilton Depression Scale is is composed of 17 questions. The total score ranges from 0 to 53. The higher the score, the more depressed the patient. In this scale, score 8-16 indicates mild severity, 17-23 represents mild to moderate severity, and 24-53 refers moderates to severe condition. | at baseline(week 0)、week 4 and week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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electroacupuncture, Randomized Controlled Trial, multi-modal magnetic resonance imaging