Botulinum Toxin A Treatment of Detrusor External Sphincter Dyssynergia During Early Spinal Cord Injury (Protocol #H-20344)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 1
- 试验地点
- 2
- 主要终点
- A Change in DLPP of 20cm H2O at Day 30 and Day 120 in the BTX-A Injected Group (Group 1) Compared to the Sham Saline Injected Group (Group 2).
研究概览
简要总结
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 (i.e. acupuncture) and wet needling (i.e. 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.
详细描述
Approximately 10,000 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 (i.e. antimuscarinic agents) or by decreasing bladder outlet resistance (i..e. 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 (i.e. interstitial cystitis). Studies have found that by inhibiting NGF's 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 (0.2 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 Allergan's 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 units/nanogram of neurotoxin protein complex.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or Females between ages of 18-50
- •Patient weighs over 111 pounds
- •Patient has documented Spinal Cord Injury T10 or above Thoracic Level by ASIA Score less than 8 weeks prior to the start of the study. Both complete and incomplete spinal cord injuries will be included in this study.
- •Ability to complete all study requirements including voiding diary and to attend all scheduled study visits, in the opinion of the investigator
- •Written informed consent has been obtained
- •Patient has negative pregnancy test result if female and of child-bearing potential
- •Written authorization for use and release of Health and Research Study Information has been obtained
- •Patient or family member is willing and able to perform clean intermittent catheterization for duration of this study
排除标准
- •Patient has received anticholinergic medication for the treatment of overactive bladder before randomization into the study
- •Patient has history or evidence of any pelvic or urological abnormalities, bladder or urethral surgery or disease, other than neurogenic bladder related to spinal cord injury, that may impact bladder function
- •Patient has significant stress urinary incontinence, determined by patient history, in the opinion of the investigator
- •Neurogenic detrusor overactivity (greater than 10cm elevation in pdet pressure) at baseline urodynamic screening (Day 0)
- •Patient found to have significant baseline renal pathology (e.g. hydronephrosis, stones, renal mass) at Day -7
- •Patient has a history of two or more treated urinary tract infections within 6 months of screening Day -7
- •Patient has urinary tract infection defined as a bacteriuria count of greater than 105/ml conjoint with leukocyturia greater than 5hpf at screening Day -7
- •Patient has asymptomatic urinary tract infection, defined as positive nitrites, leukocyte esterase and or blood on urine dipstick reagent strip at randomization Day 0
- •Patient has history of unexplained hematuria or unexplained hematuria if greater than 5 RBC's/hpf are present at screening Day -7
- •Patient has active genital infection, other than genital warts, either concurrently or within 4 weeks prior to screening Day -7
- •Patient has history of interstitial cystitis, in the opinion of the investigator
- •Patient has evidence of urethral obstruction, in the opinion of the investigator at screening Day -7 or randomization Day 0
- •Patient uses medications with anti-platelet or anti-coagulant effects (except Lovenox) within 10 days of randomization Day
- •Lovenox 30mg SQ every 12 hours is standard of care after SCI until 2-3 months post injury. Lovenox will be stopped 24 hours before and for 48 hours after each sphincter injection or bladder biopsy procedure.
- •Patient has hemophilia, or other clotting factor deficiencies or disorders that cause bleeding diathesis
- •Patient has previously been treated with any endovesical pharmacologic agent (e.g. capsaicin, resiniferatoxin)
- •Patient has had previous or current botulinum toxin therapy of any serotype for any condition
- •Patient has a known allergy or sensitivity to any components of the study medication, anesthetics or antibiotics to be used during the study
- •Any medical condition that may put the patient at increased risk with exposure to Botox® including diagnosed myasthenia gravis, Eaton-Lambert syndrome or amyotrophic lateral sclerosis
- •Females who are pregnant, nursing or planning a pregnancy during the study or females of child-bearing potential who are unable or unwilling to use a reliable form of contraception during the study
- •Current or previous participation in another therapeutic study within 30 days of screening Day -7
- •Any condition or situation which, in the investigator's opinion, puts the patient at significant risk, could confound the study results, or may interfere significantly with the patient's participation in the study
研究组 & 干预措施
ARM 2
Subjects randomized to receive placebo (saline) sham saline injections on Days 0 and 90.
干预措施: Saline injection (Other)
ARM 1
Subjects randomized to receive 100 units BOTOX-A injections on Days 0 and 90.
干预措施: BOTOX-A (Drug)
结局指标
主要结局
A Change in DLPP of 20cm H2O at Day 30 and Day 120 in the BTX-A Injected Group (Group 1) Compared to the Sham Saline Injected Group (Group 2).
时间窗: 2.5 years
This outcome measure was not able to be determined due to the subject being lost to follow-up. The subject no longer returns phone calls or visits the clinic.
次要结局
未报告次要终点
研究者
Christopher Patrick Smith
Associate Professor
Baylor College of Medicine