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

Sponsor
Buddhist Tzu Chi General Hospital (Other)
Overall Status
Completed
CT.gov ID
NCT01682603
Collaborator
(none)
34
Enrollment
1
Location
1
Arm
15
Duration (Months)
2.3
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Botulinum toxin A
 Phase 2

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
34 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Effect of Botulinum Toxin A on Detrusor Overactivity and Renal Function in Chronic Spinal Cord Injured Patients - Clinical Effects and Investigating Mechanism of Action
Study Start Date :
Sep 1, 2012
Actual Primary Completion Date :
Dec 1, 2013
Actual Study Completion Date :
Dec 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Experimental: Botulinum toxin A

BoNT-A (BOTOX 300U)

Drug: Botulinum toxin A
BoNT-A (BOTOX 300U)
Other Names:
  • BoNT-A (BOTOX 300U)

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 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

    2. 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

    3. 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

    Secondary Outcome Measures

    1. 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

    2. 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

    3. 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

    4. 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

    5. 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

    6. 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

    Other Outcome Measures

    1. Autonomic Dysreflexia [Baseline and 12 months]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    19 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Buddhist Tzu Chi General Hospital Hualien Taiwan 970

    Sponsors and Collaborators

    • Buddhist Tzu Chi General Hospital

    Investigators

    • Principal Investigator: Hann-Chorng Kuo, M.D., Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Hann-Chorng Kuo, Director of Urology, Buddhist Tzu Chi General Hospital
    ClinicalTrials.gov Identifier:
    NCT01682603
    Other Study ID Numbers:
    • TCGHUROL005
    First Posted:
    Sep 11, 2012
    Last Update Posted:
    Mar 20, 2017
    Last Verified:
    Jun 1, 2014
    Keywords provided by Hann-Chorng Kuo, Director of Urology, Buddhist Tzu Chi General Hospital
    Nerve growth factor
    P2X3 receptor
    Transient Receptor Potential Vanilloid 1 (TRPV-1) receptor
    Bladder function
    Glomerular filtration rate
    Detrusor overactivity
    Spinal cord injury
    Additional relevant MeSH terms:
    Spinal Cord Injuries
    Botulinum Toxins
    Botulinum Toxins, Type A
    abobotulinumtoxinA

    Study Results

    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 Detail 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.
    Arm/Group Title Botulinum Toxin A
    Arm/Group Description Botulinum toxin A (BoNT-A) (BOTOX 300U)
    Period Title: Overall Study
    STARTED 37
    COMPLETED 34
    NOT COMPLETED 3

    Baseline Characteristics

    Arm/Group Title Botulinum Toxin A
    Arm/Group Description BoNT-A (BOTOX 300U) Botulinum toxin A: BoNT-A (BOTOX 300U)
    Overall Participants 34
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    41.5
    Sex: Female, Male (Count of Participants)
    Female
    12
    35.3%
    Male
    22
    64.7%
    Region of Enrollment (participants) [Number]
    Taiwan
    34
    100%
    Injury Level (participants) [Number]
    Cervical
    13
    38.2%
    Thoracic
    21
    61.8%
    ASIA Classification (participants) [Number]
    A
    27
    79.4%
    B
    3
    8.8%
    C
    2
    5.9%
    D
    2
    5.9%
    Autonomic dysreflexia (participants) [Number]
    Autonomic dysreflexia
    11
    32.4%
    Non-Autonomic dysreflexia
    23
    67.6%

    Outcome Measures

    1. Primary Outcome
    Title Net Change of the Urinary Distress Inventory (UDI-6)
    Description 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
    Time Frame Baseline and 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Botulinum Toxin A
    Arm/Group Description BoNT-A (BOTOX 300U) Botulinum toxin A: BoNT-A (BOTOX 300U)
    Measure Participants 34
    Baseline
    10.4
    (4.13)
    12 months
    7.43
    (2.24)
    2. Secondary Outcome
    Title Net Change of the Cystometric Bladder Capacity (CBC)
    Description Efficacy: Net change of the cystometric bladder capacity (CBC) from baseline and 12 months Safety: Systemic adverse events
    Time Frame Baseline and 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Botulinum Toxin A
    Arm/Group Description BoNT-A (BOTOX 300U) Botulinum toxin A: BoNT-A (BOTOX 300U)
    Measure Participants 34
    Baseline
    305.9
    (167.7)
    12 months
    437.6
    (114.3)
    3. Secondary Outcome
    Title Net Change of the Bladder Compliance
    Description 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
    Time Frame Baseline and 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Botulinum Toxin A
    Arm/Group Description BoNT-A (BOTOX 300U) Botulinum toxin A: BoNT-A (BOTOX 300U)
    Measure Participants 34
    Baseline
    30.6
    (29.1)
    12 months
    29.0
    (19.6)
    4. Secondary Outcome
    Title Net Change of the Maximum Flow Rate (Qmax)
    Description Efficacy: Net change of the maximum flow rate (Qmax) from baseline and 12 months Safety: Systemic adverse events
    Time Frame Baseline and 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Botulinum Toxin A
    Arm/Group Description BoNT-A (BOTOX 300U) Botulinum toxin A: BoNT-A (BOTOX 300U)
    Measure Participants 34
    Baseline
    4.56
    (4.75)
    12 months
    3.54
    (8.85)
    5. Secondary Outcome
    Title Net Change of the Void Volume
    Description Efficacy: Net change of the void volume from baseline and 12 months Safety: Systemic adverse events
    Time Frame Baseline and 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Botulinum Toxin A
    Arm/Group Description BoNT-A (BOTOX 300U) Botulinum toxin A: BoNT-A (BOTOX 300U)
    Measure Participants 34
    Baseline
    79.6
    (95.1)
    12 months
    59.2
    (125.1)
    6. Secondary Outcome
    Title Net Change of the Detrusor Pressure (Pdet)
    Description Efficacy: Net change of the detrusor pressure (Pdet) from baseline and 12 months Safety: Systemic adverse events
    Time Frame Baseline and 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Botulinum Toxin A
    Arm/Group Description BoNT-A (BOTOX 300U) Botulinum toxin A: BoNT-A (BOTOX 300U)
    Measure Participants 34
    Baseline
    36.1
    (22.2)
    12 months
    12.9
    (16.9)
    7. Secondary Outcome
    Title Net Change of the Postvoid Residual Volume (PVR)
    Description 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
    Time Frame Baseline and 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Botulinum Toxin A
    Arm/Group Description BoNT-A (BOTOX 300U) Botulinum toxin A: BoNT-A (BOTOX 300U)
    Measure Participants 34
    Baseline
    226.3
    (138.2)
    12 months
    378.5
    (142.1)
    8. Primary Outcome
    Title Net Change of the Incontinence Impact Questionnaire (IIQ-7)
    Description 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
    Time Frame Baseline and 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Botulinum Toxin A
    Arm/Group Description BoNT-A (BOTOX 300U) Botulinum toxin A: BoNT-A (BOTOX 300U)
    Measure Participants 34
    Baseline
    11.9
    (5.22)
    12 months
    5.57
    (4.97)
    9. Primary Outcome
    Title Net Change of the Quality of Life Index (QoL-I)
    Description 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
    Time Frame Baseline and 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Botulinum Toxin A
    Arm/Group Description BoNT-A (BOTOX 300U) Botulinum toxin A: BoNT-A (BOTOX 300U)
    Measure Participants 34
    Baseline
    4.00
    (1.24)
    12 months
    2.21
    (1.48)
    10. Other Pre-specified Outcome
    Title Autonomic Dysreflexia
    Description
    Time Frame Baseline and 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pre-Autonomic Dysreflexia Pre-Non Autonomic Dysreflexia
    Arm/Group Description Baseline Autonomic dysreflexia Baseline Non autonomic dysreflexia
    Measure Participants 11 23
    Post-Autonomic dysreflexia
    5
    14.7%
    1
    NaN
    Post-Non Autonomic dysreflexia
    6
    17.6%
    22
    NaN

    Adverse Events

    Time Frame 12 months
    Adverse Event Reporting Description
    Arm/Group Title Botulinum Toxin A
    Arm/Group Description BoNT-A (BOTOX 300U) Botulinum toxin A: BoNT-A (BOTOX 300U)
    All Cause Mortality
    Botulinum Toxin A
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    Botulinum Toxin A
    Affected / at Risk (%) # Events
    Total 0/34 (0%)
    Other (Not Including Serious) Adverse Events
    Botulinum Toxin A
    Affected / at Risk (%) # Events
    Total 22/34 (64.7%)
    Nervous system disorders
    De nove autonomic dysreflexia 6/34 (17.6%)
    Renal and urinary disorders
    Difficult urination 1/34 (2.9%)
    Hematuria 5/34 (14.7%)
    Urinary tract infection 10/34 (29.4%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Hann-Chorng Kuo
    Organization Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University
    Phone 886-3-8561825 ext 2113
    Email hck@tzuchi.com.tw
    Responsible Party:
    Hann-Chorng Kuo, Director of Urology, Buddhist Tzu Chi General Hospital
    ClinicalTrials.gov Identifier:
    NCT01682603
    Other Study ID Numbers:
    • TCGHUROL005
    First Posted:
    Sep 11, 2012
    Last Update Posted:
    Mar 20, 2017
    Last Verified:
    Jun 1, 2014