Botox for Neurogenic Detrusor Overactivity and the Prevention of Autonomic Dysreflexia Following SCI
Condition: Autonomic Dysreflexia
MeSH terms: Autonomic Dysreflexia; Urinary Bladder, Overactive
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to investigate the impact of 200 U intradetrusor injected
      OnabotulinumtoxinA (Botox®, Allergan, Inc.) (20 sites, trigone sparing) for neurogenic
      detrusor overactivity (NDO) and its role on reducing autonomic dysreflexia (AD) in those with
      chronic, traumatic spinal cord injury (SCI). In clinical practice, urinary bladder
      dysfunctions are commonly associated with episodes of AD. If AD is misdiagnosed or poorly
      managed, it may result in myocardial infarction, stroke, seizure, intracerebral hemorrhaging
      or even death. Reducing AD would dramatically improve the health and well-being of Canadians
      with SCI, and positively impact health care costs. There are an estimated 7,343 hospital
      re-admissions due to SCI-related conditions in Canada every year, with an estimated 5-year
      cost of $661 million. Reducing hospital re-admissions for secondary complications of SCI by
      only 10% over this time period could result in a costs savings of $66 million for Canada.

      Considering these statistics, the present study could be a first attempt to evaluate the
      economic impact of using Botox® to manage the urinary bladder following SCI. We will be able
      to examine its impact on episodes of AD and consequently calculate the cost saving for the
      Canadian health system. A significant number of individuals with SCI will require frequent
      emergency room visits due to episodes of uncontrolled AD that originate predominately from
      the urinary bladder. There is clinical evidence demonstrating that costs of bladder
      management following SCI will depend on the understanding of the volumes that the urinary
      bladder can safely hold. This is one of the positive outcomes that have been established in
      previous trials of Botox® therapy for the neurogenic bladder.

      Hypothesis: 200 U of intradetrusor injected Botox® (20 sites, trigone sparing) for neurogenic
      bladder detrusor hyperreflexia will decrease the severity of AD in individuals with SCI one
      month following treatment.
    

Detailed description: 
      Purpose: This study is a Phase IV pilot study. A phase IV study is a study of an approved
      drug or treatment conducted to obtain information regarding the drug's or treatment's,
      benefits and optimal use. The investigators will assess the efficacy of Botox® on reducing
      autonomic dysreflexia (AD) during regular treatment for neurogenic detrusor overactivity
      (NDO) in those with spinal cord injury (SCI). The aim of the study is not to prove the
      positive/negative effects of Botox® injections on urinary bladder function (this has been
      previously been established in randomized controlled clinical trials), but to gain
      information if this intervention could ameliorate changes in arterial blood pressure (namely
      to prevent AD) that commonly occurs due to NDO. This study will particularly determine
      whether established Botox® therapy for NDO could decrease the severity of episodes of AD by
      at least 50%.

      Objective 1: The primary objective of this study is to assess the efficacy of intradetrusor
      injected Botox® on amelioration of episodes of AD in individuals with chronic SCI.

      Primary outcome:

      To assess the effect of Botox® on reducing AD as per the average systolic blood pressure
      change (maximum systolic blood pressure subtracted the average supine baseline systolic blood
      pressure) induced by urodynamics.

      The end point of the trial will be a decrease of severity of AD in 50% of participants. By
      definition AD is is a constellation of signs and/or symptoms in SCI at and usually above T6
      in response to noxious or non-noxious stimuli below the level of injury defined by an
      increase in systolic BP (>20 mmHg above baseline), including headache, flushing,
      piloerection, stuffy nose, sweating above the level of the lesion, vasoconstriction below the
      level of the lesion, and dysrhythmias.

      Episodes of AD can be triggered by a variety of causes, including those not related to
      bladder function. In order to be more focused, the investigators specifically selected as our
      primary outcome a decrease in systolic blood pressure when episodes of AD are triggered by
      urodynamics, one of the known iatrogenic causes of AD.

      Secondary outcomes:

      Objective 2. To assess the effect of Botox® on reducing AD severity and frequency during 24
      hour ambulatory blood pressure monitoring with daily catheterizations.

      Objective 3. To undertake a retrospective cost analysis of Botox® treatment on AD care
      following six months of treatment.

      Objective 4. To assess the effect of Botox® on reducing AD signs and symptoms as per
      responses on the AD health-related quality of life (AD HR-QoL) questionnaire .

      Objective 5. To assess the effect of Botox® on improving bladder-related quality of life as
      per the incontinence quality of life (I-QOL) questionnaire.

      The investigators will utilize previously established protocols in Canada for the treatment
      of NDO with Botox ® injections.

      Injections will be performed by qualified urologists (Dr. Mark Nigro, Vancouver, BC; Dr.
      Daniel Rapoport - Vancouver and Richmond, BC, and Dr. Alex Kavanagh, Vancouver, BC) at
      designated centres. Individuals will be recruited and informed consent will be obtained. The
      severity of AD will be established before treatment during standardized urodynamic
      /cystometry procedures (Drs. Nigro, Rapoport, and Kavanagh) with continuous blood pressure
      and electrocardiogram (ECG) monitoring (Dr. Krassioukov). Additionally, 24 hr ambulatory
      blood pressure and symptoms/severity of AD during catheterization and bowel routines will be
      recorded.

      OnabotulinumtoxinA (Botox®, Allergan, Inc.) Total dose (per patient): 200U Number of cycles:
      1

      Treatments will be conducted according to the previously established protocol, 200 units of
      Botox® with intradetrusor injections under cystoscopic guided injections into 20 sites,
      trigone sparing. One month later, urodynamics with continuous blood pressure and ECG
      measurements will be repeated, as well as 24 hour blood pressure monitoring and symptoms
      recording. Finally, the AD HR-QoL questionnaire will be administered to evaluate the effect
      of Botox® on AD and quality of life. I-QOL will be administered to evaluate the effect of
      Botox® on improving bladder related QoL.

      Primary efficacy variable:

      Severity of AD during urodynamics testing following the Botox® treatment. Pre - post
      comparison. Urodynamics evaluation will be conducted pre and post (1 month) Botox® injection
      (200 units into the 20 sites, trigone sparing) with continuous blood pressure and heart rate
      monitoring.

      Secondary efficacy variables:

        1. 24 hour ambulatory blood pressure monitoring will be conducted 1 week before Botox®
           injections and 1 month post Botox® treatment. Daily variations of blood pressure and
           highest blood pressure will be measured during catheterizations and bowel routines.

        2. A retrospective chart analysis of hospital admissions related to AD 6 months prior to
           receiving treatments of Botox® therapy for bladder management, and 6 months following
           the Botox® treatment, and evaluate the economical impact on health care. Cost analyses
           will be undertaken in collaboration with Dr. Stirling from the Centre for Clinical
           Epidemiology and Evaluation, School of Population and Public Health at UBC. Dr. Stirling
           is currently collaborating with Dr. Krassioukov's CIHR Cardiovascular health and SCI
           team grant.

           The objective of the cost analysis will be to estimate direct medical costs associated
           with admissions for episodes of AD before and after treatments with Botox® for the
           neurogenic bladder. This approach will establish baseline estimates that are current
           unknown, and allow for determination of cost consequences directly attributable to the
           Botox® intervention. The care cost analysis is a 3-stage process: determining relevant
           resource items, collecting data regarding units of resource use, and identifying
           appropriate unit costs. Patient-specific total cost estimates are derived by aggregating
           improved cardiovascular outcomes (decrease in severity of AD by 50%) each unit of
           resource multiplied by the respective unit cost. The benefits of patient-level cost data
           are well documented (e.g., data cleaning, investigating sources of variability).
           Accordingly, the planned micro-costing exercise will generate patient-level cost
           estimates for all admissions for episodes of AD in both the pre-treatment (6 months
           retrospective chart analysis) and post-treatment (6 months analysis) phases. This study
           design overcomes methodological problems associated with previous costing research for
           SCI, like focusing on single centers/providers or relying on patient recall of health
           care use.

        3. Statistical analysis. The primary outcome will include cardiovascular parameters and
           include baseline heart rate and arterial blood pressure (before and during urodynamics).
           Additionally, arterial blood pressure and heart rate lability will be examined by
           24-hour ambulatory blood pressure monitoring and via questionnaire to assess participant
           reported frequency and severity of AD and its impact on QoL before and after Botox® and
           bladder related health.

        4. The AD HR-QoL questionnaire will assess the impact of Botox® on improving AD-related QoL
           compared to baseline (i.e. does AD HR-QoL improve following treatment with Botox®).This
           questionnaire is based on a modified version of the reliable AD Following SCI
           Questionnaire.

        5. The I- QOL questionnaire, will also be utilized to assess the impact of Botox® on
           improving bladder-related QoL.
    

Intervention name(s): BOTOX
Intervention type(s): Drug
Intervention description(s): BOTOX® Total dose per patient: 200U Number of cycles:1 cycle
200 units of BOTOX® will be injected per procedure. BOTOX® will be diluted in 15mL saline to 20U/mL. BOTOX® injections will be performed with a normal 22 FF rigid cystoscopy or flexible 6Fr injection needle. BOTOX® will be injected into the detrusor muscle at 20 sites (10U per site), sparing the trigone. A local anaesthesia with instillation of 50 ml lidocaine 2% into the bladder will be done prior to the procedure to avoid autonomic dysreflexia.
Other intervention name(s): Botulinum toxin Type A, BTX-A,
Intervention MeSH terms: Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Autonomic Dysreflexia; Spinal Cord Injury; OnabotulinumtoxinA; Neurogenic Detrusor Overactivity; Urodynamics; Cardiovascular; Quality of Life; Blood Pressure; 24 Hour Ambulatory Blood Pressure Monitoring