Ignite Creation Date:
2024-05-05 @ 7:41 PM
Last Modification Date:
2024-10-26 @ 9:51 AM
Study NCT ID:
NCT00711087
Status:
TERMINATED
Last Update Posted:
2021-01-06
First Post:
2008-07-07
Brief Title:
Botox-A Injection to Improve Bladder Function in Early Spinal Cord Injury H-20344
Sponsor:
Baylor College of Medicine
Organization:
Baylor College of Medicine
Study Overview
Official Title:
Botulinum Toxin A Treatment of Detrusor External Sphincter Dyssynergia During Early Spinal Cord Injury Protocol H-20344
Status:
TERMINATED
Status Verified Date:
2021-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Funds no longer available
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this study is to see what the effect of Botox has on bladder function for those who have recently suffered spinal cord injury We also will study bladder tissue levels of NGF nerve growth factor that can tell us how the nerves to the bladder are healing after injury
Consenting male and female cervical and high thoracic T10 and above SCI patients will be identified within the first 6-7 weeks after SCI and randomized to two external urethral sphincter injection groups Each group will be injected within 8 weeks after SCI Day 0 and 3 months later Day 90 The injection paradigm will consist of Group 1-100 units of BTX-A Botox Allergan Inc Irvine CA on Day 0 and 100 units of BTX-A on Day 90 Group 2-sham saline injections on both Day 0 and Day 90 Injections will be performed under local anesthesia using standard flexible cystoscopic equipment
Use of placebo is justified because 1 there have been documentation of nerve desensitization with dry needling ie acupuncture and wet needling ie saline--therefore to truly demonstrate benefit of Botox over just the needle insertion into the sphincter muscle or injection of the diluent saline a sham saline injection group is included 2 the injection procedure itself is minimally invasive and not expected to result in any complications
Subjects who qualify and have signed the informed consent document will be randomized into two groups those receiving the BTX-A and those receiving placebo Blinding will be performed by the TIRR pharmacy department who will provide Botox and placebo in identical syringes so that the treating staff will be blinded Pharmacists will ensure patients receive the same agent at the time of the second injection Unblinding will occur at the end of the study or if complications necessitate breaking of the code Both groups will undergo urodynamic testing to document before and after treatment data Bladder biopsies will be taken prior to treatment in both groups that will be analyzed for nerve growth factor Three day voiding diaries will be kept and reviewed with the study coordinator at the follow up visits Quality of life questionnaires will be completed at each follow up visit The treatments will take place on Day 0 and Day 90 Follow up visits will occur at Day 120 16 month and 28 months
Consenting male and female cervical and high thoracic T10 and above SCI patients will be identified within the first 6-7 weeks after SCI and randomized to two external urethral sphincter injection groups Each group will be injected within 8 weeks after SCI Day 0 and 3 months later Day 90 The injection paradigm will consist of Group 1-100 units of BTX-A Botox Allergan Inc Irvine CA on Day 0 and 100 units of BTX-A on Day 90 Group 2-sham saline injections on both Day 0 and Day 90 Injections will be performed under local anesthesia using standard flexible cystoscopic equipment
Use of placebo is justified because 1 there have been documentation of nerve desensitization with dry needling ie acupuncture and wet needling ie saline--therefore to truly demonstrate benefit of Botox over just the needle insertion into the sphincter muscle or injection of the diluent saline a sham saline injection group is included 2 the injection procedure itself is minimally invasive and not expected to result in any complications
Subjects who qualify and have signed the informed consent document will be randomized into two groups those receiving the BTX-A and those receiving placebo Blinding will be performed by the TIRR pharmacy department who will provide Botox and placebo in identical syringes so that the treating staff will be blinded Pharmacists will ensure patients receive the same agent at the time of the second injection Unblinding will occur at the end of the study or if complications necessitate breaking of the code Both groups will undergo urodynamic testing to document before and after treatment data Bladder biopsies will be taken prior to treatment in both groups that will be analyzed for nerve growth factor Three day voiding diaries will be kept and reviewed with the study coordinator at the follow up visits Quality of life questionnaires will be completed at each follow up visit The treatments will take place on Day 0 and Day 90 Follow up visits will occur at Day 120 16 month and 28 months
Detailed Description:
Approximately 10000 spinal cord injuries SCI occur each year most of which occur in males 80 Many of these patients develop neurogenic bladder dysfunction NGB characterized by overactivity of the detrusor muscle termed detrusor overactivity DO or detrusor hyperreflexia DH They can also develop detrusor external sphincter dyssynergia DESD an abnormal uncoordinated response of the sphincter to bladder contraction A combination of these factors can lead to long-term complications in up to 50 of patients These complications include hydronephrosis autonomic dysreflexia vesicoureteral reflux nephrolithiasis sepsis renal insufficiency or failure and even death Our basic understanding of the physiology of NGB as well as the introduction of the concept of clean intermittent catheterization CIC several decades ago has significantly reduced the death rate due to renal complications in SCI patients Nevertheless there continues to be a significant amount of morbidity and risk that these patients experience due to our incomplete understanding of DESD both its development and subsequent impact on bladder function We postulate that a primary drive to producing detrusor hypercontractility is the obstruction created by increased tone within the external urethral sphincter EUS In addition we hypothesize that high-pressure obstructive voiding patterns displayed by patients with DESD promote development of bladder wall smooth muscle hypertrophy and fibrosis loss of bladder compliance and development of the complications listed above
Most of our treatment options for neurogenic bladder in the SCI patient population aim to reduce bladder filling pressures and obstructive voiding patterns either by reducing bladder overactivity ie antimuscarinic agents or by decreasing bladder outlet resistance ie alpha 1-adrenergic receptor antagonists sphincterotomy UroLume stent placement or botulinum toxin injection of external urethral sphincter However typically treatments are not initiated until these reflex voiding patterns have already developed Almost all patients with supraconal lesions regardless of their neurological level of injury or final voiding patterns display areflexic bladders during the acute and subacute time period after SCI This time period can last anywhere from 1 month to 1 year typically 6-8 weeks after which spinal reflex voiding develops Dyssynergic voiding patterns are most common in cervical and thoracic supraconal lesions while are flexic voiding patterns predominate in lumbar and sacral conal and infraconal injuries However there are many exceptions to this rule especially in incomplete lesions and that is why urodynamic testing is an important component in the evaluation of every SCI patient
Nerve Growth Factor NGF Role in Obstructive Uropathy The processes that lead to reorganization of neural pathways and emergence of hyperactive and dyssynergic voiding are incompletely understood Possible mechanisms underlying the neural plasticity following SCI could involve alterations in levels of neurotrophic factors within the bladder Nerve Growth Factor NGF is a signaling protein that is thought to play a prominent role in mediating the development of bladder reflex voiding mechanisms in various disorders of bladder dysfunction including neurogenic and non-neurogenic bladder outlet obstruction and chronic bladder inflammation ie interstitial cystitis Studies have found that by inhibiting NGFs actions through immunization enhancement of bladder hyperactivity and detrusor sphincter dyssynergia was prevented in SCI rats Finally studies in SCI human patients found that bladder hyperactivity as well as bladder NGF tissue levels was significantly reduced by bladder BTX-A treatment
BOTOX Botulinum Toxin Type A Purified Neurotoxin Complex is a sterile vacuum-dried purified botulinum toxin type A produced from fermentation of Hall strain Clostridium botulinum type A grown in a medium containing casein hydrolysate glucose and yeast extract It is purified from the culture solution by dialysis and a series of acid precipitations to a complex consisting of the neurotoxin and several accessory proteins The complex is dissolved in sterile sodium chloride solution containing Albumin Human and is sterile filtered 02 microns prior to filling and vacuum-drying
One Unit of BOTOX corresponds to the calculated median intraperitoneal lethal dose LD50 in mice The method utilized for performing the assay is specific to Allergans product BOTOX Due to specific details of this assay such as the vehicle dilution scheme and laboratory protocols for the various mouse LD50 assays Units of biological activity of BOTOX cannot be compared to nor converted into Units of any other botulinum toxin or any toxin assessed with any other specific assay method Therefore differences in species sensitivities to different botulinum neurotoxin serotypes precludes BOTOX is approximately 20 unitsnanogram of neurotoxin protein complex
Each vial of BOTOX contains 100 Units U of Clostridium botulinum type A neurotoxin complex 05 milligrams of Albumin Human and 09 milligrams of sodium chloride in a sterile vacuum-dried form without a preservative
Botulinum Toxin BTX-A to treat DESD Botulinum toxin first isolated by van Ermengem in 1897 is the most potent biological toxin known to man Through basic and clinical research clinicians have been able to transform this lethal toxin into a health benefit BTX-A represents a viable option in the treatment of DESD When injected the toxin acts at the neuromuscular junction of the external sphincter to block vesicle transport of acetylcholine in essence producing a chemical denervation The clinical effects begin within 2-3 days and are reversible as terminal nerve sprouting occurs within 3-6 months
The majority of studies on DESD have examined several outcome measures following BTX-A injection Change in post-void residual PVR change in urethral pressure profile UPP-static or dynamic change in bladder pressures during voiding change in frequency or severity of autonomic dysreflexia AD and change in symptoms or satisfaction of the procedure to the patient Once again BTX-A treated patients demonstrated improvements in PVR and UPP similar to their previous study
However while most studies of BTX-A for DESD have documented significant reductions in detrusor and urethral pressures as well as PVR prior research has shown that detrusor leak point pressure DLPP is the best prognostic measure for upper tract damage in neurogenic bladder patients This fundamental concept was corroborated by external sphincterotomy studies demonstrating that failure to achieve a DLPP below 40 cm H2O increases the frequency of upper tract deterioration This finding underscores the importance that future studies examining the efficacy of BTX treatment for DESD will utilize DLPP as an objective measure of the procedures success
Preliminary Data Effect of BTX-A on Urethral Outlet Resistance by Measuring Changes in Leak Point Pressure The purpose of these investigations was to evaluate the effects of BTX-A on in vivo urethral resistance by measuring leak point pressure LPP with a vertical tilt table and intravesical pressure clamp
Female SD rats n8 220-250g were anesthetized with urethane 12 gkg and injected intraperitoneally with either BTX-A 100u or saline 18 hours prior to experimentation LPP was recorded before and after administration of the nicotinic receptor antagonist -bungarotoxin BGT and the ganglionic blocker hexamethonium HEX
BGT significantly decreased the LPP in control animals by 46 but had no appreciable affect in BTX-A treated animals In comparison BTX-A treatment decreased LPP by 47 compared to baseline values in control animals The ganglionic blocker HEX had no appreciable effect on either control or BTX-A treated animals
BTX-A significantly decreased the basal LPP to the same extent as BGT confirming its in vivo potency at the striated neuromuscular junction However the fact that HEX had no appreciable effect in either group suggests that sympathetic tone is not a prominent component of outlet resistance in female rats and may not be a suitable in vivo model to describe the effects of BTX-A on urethral adrenergic pathways Although originally designed as a method to evaluate stress urinary incontinence in rodents this method actually measures the intravesical pressure during bladder filling at which urinary leakage occurs that is detrusor leak point pressure DLPP The marked decrease in DLPP induced by BTX-A in this animal model validates BTX-As potential effects on DLPP in humans with DESD
BTX-A Urethral Sphincter Injections in Humans Sixty eight patients received urethral sphincter injections for bladder outlet obstruction resulting from DESD or pelvic floor spasticity Patients mean age was 53 range 21-71 and the underlying pathophysiology for outlet obstruction included spinal cord injury n9 multiple sclerosis n32 stroke n4 other n8 idiopathic retentionpelvic floor spasticity n15 Patients were injected with 100 units of BTX-A into their external urethral sphincters under local or general anesthesia Postoperatively significant decreases in maximal detrusor pressures 81cm to 52cm H2O p005 and post-void residuals 240ml to 88ml p005 were observed with beneficial effects lasting 3-4 months
Significance The significance of these experiments begins with the fact that our proposed intervention occurs during early spinal cord injury ie within 8 weeks before pathologic bladder reflex pathways have emerged In addition our proposed project would be 1 The largest prospective randomized trial examining the effects of BTX-A urethral sphincter injection for detrusor external sphincter dyssynergia DESD and the first to look at the effect of BTX-A on detrusor leak point pressure DLPP 2 The first study to evaluate the role that bladder outlet obstruction by DESD plays in the development of bladder hyperactivity and the development of complications resulting from bladder dysfunction 3 The first study profiling bladder tissue levels of the signaling protein nerve growth factor NGF during early SCI and then again once bladder hyperreflexic patterns develop and 4 The first study evaluating the effect of reducing outlet resistance with BTX-A on bladder NGF levels If our hypotheses prove to be correct treated patients will display less incontinence require lower doses of anticholinergic medication and avoid the complications of DESD listed earlier in this proposal Although this study as written is of moderate length ie total 5 years we hope that by finding significant results we will be able to capture a longitudinal history of this population by extending follow-up to a longer duration ie 10 years In addition BTX-A treatment could be extended to other neurogenic populations suffering from DESD ie Multiple Sclerosis as well as other conditions where bladder overactivity appears to be driven by outlet obstruction ie Benign Prostatic Hyperplasia
Hypotheses
1 BTX-A injection of the external urethral sphincter significantly decreases detrusor leak point pressure DLPP
2 Decreased DLPP during early SCI will markedly reduce bladder tissue nerve growth factor NGF
3 Reducing DLPP and bladder NGF during early SCI will diminish complications associated with neurogenic detrusor overactivity NDO and outlet obstruction
Most of our treatment options for neurogenic bladder in the SCI patient population aim to reduce bladder filling pressures and obstructive voiding patterns either by reducing bladder overactivity ie antimuscarinic agents or by decreasing bladder outlet resistance ie alpha 1-adrenergic receptor antagonists sphincterotomy UroLume stent placement or botulinum toxin injection of external urethral sphincter However typically treatments are not initiated until these reflex voiding patterns have already developed Almost all patients with supraconal lesions regardless of their neurological level of injury or final voiding patterns display areflexic bladders during the acute and subacute time period after SCI This time period can last anywhere from 1 month to 1 year typically 6-8 weeks after which spinal reflex voiding develops Dyssynergic voiding patterns are most common in cervical and thoracic supraconal lesions while are flexic voiding patterns predominate in lumbar and sacral conal and infraconal injuries However there are many exceptions to this rule especially in incomplete lesions and that is why urodynamic testing is an important component in the evaluation of every SCI patient
Nerve Growth Factor NGF Role in Obstructive Uropathy The processes that lead to reorganization of neural pathways and emergence of hyperactive and dyssynergic voiding are incompletely understood Possible mechanisms underlying the neural plasticity following SCI could involve alterations in levels of neurotrophic factors within the bladder Nerve Growth Factor NGF is a signaling protein that is thought to play a prominent role in mediating the development of bladder reflex voiding mechanisms in various disorders of bladder dysfunction including neurogenic and non-neurogenic bladder outlet obstruction and chronic bladder inflammation ie interstitial cystitis Studies have found that by inhibiting NGFs actions through immunization enhancement of bladder hyperactivity and detrusor sphincter dyssynergia was prevented in SCI rats Finally studies in SCI human patients found that bladder hyperactivity as well as bladder NGF tissue levels was significantly reduced by bladder BTX-A treatment
BOTOX Botulinum Toxin Type A Purified Neurotoxin Complex is a sterile vacuum-dried purified botulinum toxin type A produced from fermentation of Hall strain Clostridium botulinum type A grown in a medium containing casein hydrolysate glucose and yeast extract It is purified from the culture solution by dialysis and a series of acid precipitations to a complex consisting of the neurotoxin and several accessory proteins The complex is dissolved in sterile sodium chloride solution containing Albumin Human and is sterile filtered 02 microns prior to filling and vacuum-drying
One Unit of BOTOX corresponds to the calculated median intraperitoneal lethal dose LD50 in mice The method utilized for performing the assay is specific to Allergans product BOTOX Due to specific details of this assay such as the vehicle dilution scheme and laboratory protocols for the various mouse LD50 assays Units of biological activity of BOTOX cannot be compared to nor converted into Units of any other botulinum toxin or any toxin assessed with any other specific assay method Therefore differences in species sensitivities to different botulinum neurotoxin serotypes precludes BOTOX is approximately 20 unitsnanogram of neurotoxin protein complex
Each vial of BOTOX contains 100 Units U of Clostridium botulinum type A neurotoxin complex 05 milligrams of Albumin Human and 09 milligrams of sodium chloride in a sterile vacuum-dried form without a preservative
Botulinum Toxin BTX-A to treat DESD Botulinum toxin first isolated by van Ermengem in 1897 is the most potent biological toxin known to man Through basic and clinical research clinicians have been able to transform this lethal toxin into a health benefit BTX-A represents a viable option in the treatment of DESD When injected the toxin acts at the neuromuscular junction of the external sphincter to block vesicle transport of acetylcholine in essence producing a chemical denervation The clinical effects begin within 2-3 days and are reversible as terminal nerve sprouting occurs within 3-6 months
The majority of studies on DESD have examined several outcome measures following BTX-A injection Change in post-void residual PVR change in urethral pressure profile UPP-static or dynamic change in bladder pressures during voiding change in frequency or severity of autonomic dysreflexia AD and change in symptoms or satisfaction of the procedure to the patient Once again BTX-A treated patients demonstrated improvements in PVR and UPP similar to their previous study
However while most studies of BTX-A for DESD have documented significant reductions in detrusor and urethral pressures as well as PVR prior research has shown that detrusor leak point pressure DLPP is the best prognostic measure for upper tract damage in neurogenic bladder patients This fundamental concept was corroborated by external sphincterotomy studies demonstrating that failure to achieve a DLPP below 40 cm H2O increases the frequency of upper tract deterioration This finding underscores the importance that future studies examining the efficacy of BTX treatment for DESD will utilize DLPP as an objective measure of the procedures success
Preliminary Data Effect of BTX-A on Urethral Outlet Resistance by Measuring Changes in Leak Point Pressure The purpose of these investigations was to evaluate the effects of BTX-A on in vivo urethral resistance by measuring leak point pressure LPP with a vertical tilt table and intravesical pressure clamp
Female SD rats n8 220-250g were anesthetized with urethane 12 gkg and injected intraperitoneally with either BTX-A 100u or saline 18 hours prior to experimentation LPP was recorded before and after administration of the nicotinic receptor antagonist -bungarotoxin BGT and the ganglionic blocker hexamethonium HEX
BGT significantly decreased the LPP in control animals by 46 but had no appreciable affect in BTX-A treated animals In comparison BTX-A treatment decreased LPP by 47 compared to baseline values in control animals The ganglionic blocker HEX had no appreciable effect on either control or BTX-A treated animals
BTX-A significantly decreased the basal LPP to the same extent as BGT confirming its in vivo potency at the striated neuromuscular junction However the fact that HEX had no appreciable effect in either group suggests that sympathetic tone is not a prominent component of outlet resistance in female rats and may not be a suitable in vivo model to describe the effects of BTX-A on urethral adrenergic pathways Although originally designed as a method to evaluate stress urinary incontinence in rodents this method actually measures the intravesical pressure during bladder filling at which urinary leakage occurs that is detrusor leak point pressure DLPP The marked decrease in DLPP induced by BTX-A in this animal model validates BTX-As potential effects on DLPP in humans with DESD
BTX-A Urethral Sphincter Injections in Humans Sixty eight patients received urethral sphincter injections for bladder outlet obstruction resulting from DESD or pelvic floor spasticity Patients mean age was 53 range 21-71 and the underlying pathophysiology for outlet obstruction included spinal cord injury n9 multiple sclerosis n32 stroke n4 other n8 idiopathic retentionpelvic floor spasticity n15 Patients were injected with 100 units of BTX-A into their external urethral sphincters under local or general anesthesia Postoperatively significant decreases in maximal detrusor pressures 81cm to 52cm H2O p005 and post-void residuals 240ml to 88ml p005 were observed with beneficial effects lasting 3-4 months
Significance The significance of these experiments begins with the fact that our proposed intervention occurs during early spinal cord injury ie within 8 weeks before pathologic bladder reflex pathways have emerged In addition our proposed project would be 1 The largest prospective randomized trial examining the effects of BTX-A urethral sphincter injection for detrusor external sphincter dyssynergia DESD and the first to look at the effect of BTX-A on detrusor leak point pressure DLPP 2 The first study to evaluate the role that bladder outlet obstruction by DESD plays in the development of bladder hyperactivity and the development of complications resulting from bladder dysfunction 3 The first study profiling bladder tissue levels of the signaling protein nerve growth factor NGF during early SCI and then again once bladder hyperreflexic patterns develop and 4 The first study evaluating the effect of reducing outlet resistance with BTX-A on bladder NGF levels If our hypotheses prove to be correct treated patients will display less incontinence require lower doses of anticholinergic medication and avoid the complications of DESD listed earlier in this proposal Although this study as written is of moderate length ie total 5 years we hope that by finding significant results we will be able to capture a longitudinal history of this population by extending follow-up to a longer duration ie 10 years In addition BTX-A treatment could be extended to other neurogenic populations suffering from DESD ie Multiple Sclerosis as well as other conditions where bladder overactivity appears to be driven by outlet obstruction ie Benign Prostatic Hyperplasia
Hypotheses
1 BTX-A injection of the external urethral sphincter significantly decreases detrusor leak point pressure DLPP
2 Decreased DLPP during early SCI will markedly reduce bladder tissue nerve growth factor NGF
3 Reducing DLPP and bladder NGF during early SCI will diminish complications associated with neurogenic detrusor overactivity NDO and outlet obstruction
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None