Effect of Botulinum Toxin A on Detrusor Overactivity and Renal Function in Chronic Spinal Cord Injured Patients

Effect of Botulinum Toxin A on Detrusor Overactivity and Renal Function in Chronic Spinal Cord Injured Patients - Clinical Effects and Investigating Mechanism of Action

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01682603

Enrollment

Registered

2012-09-11

Start date

2012-09-30

Completion date

2013-12-31

Last updated

2017-03-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Spinal Cord Injuries

Keywords

Nerve growth factor, P2X3 receptor, Transient Receptor Potential Vanilloid 1 (TRPV-1) receptor, Bladder function, Glomerular filtration rate, Detrusor overactivity, Spinal cord injury

Brief summary

To investigate the clinical effect of detrusor botulinum toxin A (BoNT-A) injection on neurogenic detrusor overactivity (NDO) and renal function and to compare the difference of expressions of sensory receptors and nerve growth factor (NGF) in the bladder wall of patients respond and not respond to BoNT-A injections in chronic spinal cord injured (SCI) patients.

Detailed description

Study Procedure A total of 30 patients with chronic suprasacral cord SCI will be enrolled in this study. All patients are more than 18 years old and have chronic suprasacral cord injury for more than 1 year. They have previously underwent an urodynamic study and have been proven having detrusor sphincter dyssynergia (DSD). The patients currently void by reflex, abdominal stimulation or clean intermittent catheterization (CIC), are free of indwelling catheter or cystostomy, and free of urinary tract infection (UTI) on their enrollment. During the screening period, a total glomerular filtration rate (GFR) should be less than 80 mL/min as measured by 99mTc-labelled diethylenetriamine pentaacetic acid (99mTc-DTPA) clearance renal scanning. Patients should also have adequate hand function or have a care-giver available for CIC. Other exclusion criteria include patients with detrusor underactivity and large bladder compliance, patients proven to have intrinsic sphincteric deficiency and patients who have hypersensitivity to botulinum toxin A (BTX-A) or constituent ingredients of BTX-A. BTX-A injection will be performed in the operation room under light intravenous general anesthesia to prevent autonomic dysreflexia and hyperreflexia during cystoscopy. A total of 300U BTX-A (BOTOX, 100 U/vial, Allergan Co., Irvine, USA) dissolved into 30 mL normal saline will be injected into 30 sites of the bladder including lateral, posterior wall and dome. The injection sites are widely distributed to cover the whole bladder wall. A 14 Fr Foley catheter will be routinely inserted after BTX-A injection and patients will be discharged the next morning and followed up at out-patient clinic. All patients will be instructed to keep on CIC or abdominal stimulation as they previously performed. BTX-A injections will be repeated 6 months after the first treatment, then follow up to 24 months. Before each BTX-A injection a videourodynamic study and GFR test will be performed. Patients were also requested to report the severity of urinary incontinence by the mean daily incontinence episodes within three days, Urogenital Distress Inventory (UDI-6 Short Form), Incontinence Impact Questionnaire (IIQ-7), self assessed QoL index and the global satisfaction rate (graded as 0 to 3, indicating none, mild, moderate and very satisfied) to this treatment. The adverse events such as urinary tract infection, hematuria, difficult urination are also recorded. This study should be approved by the Institutional Review Board and Ethics Committee of the hospital. Informed consent will be obtained before the screening and all patients are instructed about the possible complications related with BTX-A injection such as urinary retention, transient hematuria and subsequent urinary tract infection. Patients will be classified as responders and non-responders according to their clinical presentation and urodynamic study results. Responders are considered if they become dry or reduction of incontinence episodes by 50% and have a decrease of detrusor pressure reduction by 50% of the baseline value, otherwise, they are considered as non-responders. The end-point is set at 6 months after the BTX-A injection. There were two primary end-points: (1) the net change of the IIQ-7 and UDI-6 from baseline to 24 months, and (2) the net change of the GFR from baseline to 24 months. Secondary end-point efficacy measured the net change of the cystometric bladder capacity, bladder compliance, detrusor pressure during reflex voiding, end-filling pressure or detrusor leak-point pressure and postvoid residual volume from baseline to 24 months. Three bladder biopsies using a small cystoscopic biopsy forceps will be performed in all patients. The biopsy will be performed at baseline and each time-point just prior to intravesical BTX-A injection. The bladder biopsy specimens will be sent to pathological department for H-E staining to exclude the possibility of carcinoma in situ, and also will be embedded in O.C.T. medium and stored at -80℃ refrigerator or liquid nitrogen tank for investigations. The bladder biopsies will be prepared for measurement of NGF messenger RNA (mRNA) and immunohistochemistry investigation of the expression of Transient Receptor Potential Vanilloid 1 (TRPV-1), purinergic receptor P2X, ligand-gated ion channel, 3 (P2X3) receptors at baseline and 6 months after each BTX-A injection, and the difference of these sensory protein expressions between responders and .non-responders to BTX-A injection.

Interventions

DRUGBotulinum toxin A

BoNT-A (BOTOX 300U)

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

19 Years to 65 Years

Healthy volunteers

Inclusion criteria

* Adults with age of 19 years old or above * Patients with chronic suprasacral cord SCI will be enrolled. * Patients will be proven having NDO by videourodynamic study during the screening period. * They also receive 99mTc-DTPA renal scanning for GFR at baseline. * Patients with NDO induced urinary incontinence who have adequate hand function or have a care-giver available for CIC, and the baseline total GFR of less than 80 mL/min are main inclusion criteria

Exclusion criteria

* Patients with detrusor underactivity and large bladder compliance, patients proven to have intrinsic sphincteric deficiency * Patients who have hypersensitivity to BTX-A or constituent ingredients of BTX-A.

Design outcomes

Primary

Measure	Time frame	Description
Net Change of the Quality of Life Index (QoL-I)	Baseline and 12 months	Efficacy: Net change of the quality of life index (QoL-I) from baseline and 12 months. The QoL-I on a 7-point scale ranging from 0 Delighted to 6 Terrible. The QoL-I ranges 0 to 6 Safety: Systemic adverse events
Net Change of the Urinary Distress Inventory (UDI-6)	Baseline and 12 months	Efficacy: Net change of the UrinaryDdistress Inventory (UDI-6) from baseline and 12 months. The UDI-6 is a 6-item short forms on a 4-point scale ranging from 0 Not at all to 3 Greatly. The total UDI-6 score can therefore range from 0 to 18 (asymptomatic to very symptomatic). Safety: Systemic adverse events
Net Change of the Incontinence Impact Questionnaire (IIQ-7)	Baseline and 12 months	Efficacy: Net change of the Incontinence Impact Questionnaire (IIQ-7) from baseline and 12 months. The IIQ-7 is a 7-item short forms on a 4-point scale ranging from 0 Not at all to 3 Greatly. Total IIQ-7 score ranges = 0 to 21 The total IIQ-7 score can therefore range from 0 to 21 (asymptomatic to very symptomatic). Safety: Systemic adverse events

Secondary

Measure	Time frame	Description
Net Change of the Maximum Flow Rate (Qmax)	Baseline and 12 months	Efficacy: Net change of the maximum flow rate (Qmax) from baseline and 12 months Safety: Systemic adverse events
Net Change of the Void Volume	Baseline and 12 months	Efficacy: Net change of the void volume from baseline and 12 months Safety: Systemic adverse events
Net Change of the Postvoid Residual Volume (PVR)	Baseline and 12 months	Efficacy: Net change of the postvoid residual volume (PVR) from baseline and 12 months Results: Botulinum toxin A injection have increased postvoid residual urine volume in patients treated for bladder dysfunction. Treat only patients who are willing and able to initiate catheterization post-treatment, if required, for urinary retention. Safety: Systemic adverse events
Net Change of the Detrusor Pressure (Pdet)	Baseline and 12 months	Efficacy: Net change of the detrusor pressure (Pdet) from baseline and 12 months Safety: Systemic adverse events
Net Change of the Cystometric Bladder Capacity (CBC)	Baseline and 12 months	Efficacy: Net change of the cystometric bladder capacity (CBC) from baseline and 12 months Safety: Systemic adverse events
Net Change of the Bladder Compliance	Baseline and 12 months	Bladder compliance is the result of a mathematical calculation of the volume required for a unit rise of pressure measured during a cystometric filling. Bladder compliance is calculated by dividing the volume change by the change in bladder pressure (mL/cmH2O). Efficacy: Net change of the bladder compliance from baseline and 12 months Safety: Systemic adverse events

Other

Measure	Time frame
Autonomic Dysreflexia	Baseline and 12 months

Countries

Taiwan

Participant flow

Recruitment details

The chronic SCI patients with urinary incontinence in Hualien Tzu Chi General Hospital were consecutively recruited into this study.

Pre-assignment details

Patients were excluded if they had an active urinary tract infection, urinary tract cancer, history of lower urinary tract surgery or chronic systemic diseases. If patients fulfilled the inclusion criteria, they were enrolled in this study.

Participants by arm

Arm	Count
Botulinum Toxin A BoNT-A (BOTOX 300U) Botulinum toxin A: BoNT-A (BOTOX 300U)	34
Total	34

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Lost to Follow-up	3

Baseline characteristics

Characteristic	Botulinum Toxin A
Age, Continuous	41.5 years
ASIA Classification A	27 participants
ASIA Classification B	3 participants
ASIA Classification C	2 participants
ASIA Classification D	2 participants
Autonomic dysreflexia Autonomic dysreflexia	11 participants
Autonomic dysreflexia Non-Autonomic dysreflexia	23 participants
Injury Level Cervical	13 participants
Injury Level Thoracic	21 participants
Region of Enrollment Taiwan	34 participants
Sex: Female, Male Female	12 Participants
Sex: Female, Male Male	22 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	22 / 34
serious Total, serious adverse events	0 / 34

Outcome results

Primary

Net Change of the Incontinence Impact Questionnaire (IIQ-7)

Efficacy: Net change of the Incontinence Impact Questionnaire (IIQ-7) from baseline and 12 months. The IIQ-7 is a 7-item short forms on a 4-point scale ranging from 0 Not at all to 3 Greatly. Total IIQ-7 score ranges = 0 to 21 The total IIQ-7 score can therefore range from 0 to 21 (asymptomatic to very symptomatic). Safety: Systemic adverse events