Clinical trial NCT02078895: Randomization of Botox for Stent Pain and Irritative Voiding Symptoms
Official title: Prospective Randomized Evaluation of Peri-Ureteral and Intradetrusor Injection of Botulinum Toxin Type A for the Treatment of Ureteral Stent Related Pain and Irritative Voiding Symptoms
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Lower Urinary Tract Discomfort
Stent Pain
Keywords: Lower Urinary tract discomfort , ureteral stent pain
Lead sponsor: University of California, Irvine
Sponsor class: OTHER
First posted: 2014-03-05
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Botulinum toxin type A (Botox A) has shown great success in treating certain urologic conditions. A recent study has documented that Botox injected around the ureteral orifice (or place where the tube that connects the kidney to the bladder enters the bladder), during placement of a ureteral stent (small rubber tube that facilitate drainage of urine from the kidney to the bladder), resulted in a marked decline in the amount of stent pain experienced by patients. This finding was quite remarkable as stents are commonly used in many Urologic conditions, and these stents produce a remarkable degree of patient discomfort. Despite the great improvement in pain reduction, the irritative voiding symptoms \[frequent need to void, urgency, burning with urination (dysuria) or nighttime voiding (nocturia)\] were not ameliorated by the Botox injections in the ureteral orifice. However, it has already been well documented that in other clinical settings, administrations of Botox into the bladder muscle, has been shown to reduce these irritative symptoms.

The objective of the study is to determine if pain and irritative lower urinary tract symptoms related to ureteral stent placement will improve after the injection of Botox around the ureteral orifice and in the bladder itself.

Detailed description: The objective of this prospective randomized single blinded controlled pilot study for patients undergoing unilateral ureteral stent insertion for benign urologic conditions is to determine if pain and irritative lower urinary tract symptoms (frequency, urgency, dysuria, nocturia) related to ureteral stent placement will improve after the injection of intradetrusor Botox (BTX) A.

The effects of BTX have been used for a number of medicinal purposes, including reducing wrinkles, migraine headaches, and excessive sweating. The use of BTX in urology and, more specifically, the lower urinary tract, is increasing. Botox is currently actively being used as a treatment strategy for use in Urologic conditions including neurogenic and non-neurogenic overactive bladder (OAB), detrusor sphincter dyssynergia, interstitial cystitis, urinary retention, and prostate disorders.

BTX serotypes. The seven distinct serotypes of BTX are designated A, B, C1, E, F, and G; BTX-A (Botox \[Allergan, Inc., Irvine, Calif\] and Dysport \[Ipsen, Inc., Europe\]) and BTX-B (Myobloc (Solstice Neurosciences, Inc., Malvern, Pa) are available commercially. Each serotype of botulinum toxin works by inhibiting the release of neurotransmitters, most notably acetylcholine, from the presynaptic neuromuscular junction (2). The result is inhibition of muscular contractions and paralysis.

In August 2011, the FDA recently approved the use of Botox injections for urinary incontinence secondary to neurogenic overactive bladder, a condition defined as unihibited bladder contractions causing voiding and creating symptoms of urinary frequency. The cause of the neurogenic overactive bladder in the patients studied was spinal cord injury and multiple sclerosis. Numerous prospective clinical trials have demonstrated a statistically significant difference of symptoms in patients receiving Botox injections into the overactive detrusor muscle compared to placebo groups. Botox injections were found to effectively relieve urinary incontinence and urinary frequency for a nine-month duration.

As part of standard clinical care, intravesical injection of Botox is currently used to ameliorate voiding symptoms in conditions where patients experience severe irritative symptoms and is currently seeking FDA approval for the treatment of overactive bladder in patients without a neurologic etiology. As a follow up study, we will evaluate the efficacy of combined periureteral and intravesical Botox injection for reduction of pain and irritative voiding

This is a prospective randomized single blinded controlled study for patients undergoing unilateral ureteral stent insertion for a benign urologic conditions is to determine if pain and irritative lower urinary tract symptoms (frequency, urgency, dysuria, nocturia) related to ureteral stent placement will improve after the injection of intradetrusor Botox A.

Study in detail:

All patients will be informed regarding the content of the study and informed consent will be obtained. Patients who require stent placement will be screened based on their past medical history and will be included in the study if they do not fit any of the exclusion criteria. The participation in the study will require 3 visits in addition to pre-op visit when the consent will be obtained: stent placement, stent removal, and 2 week post-op follow up. Patients will only have one pre-operative visit prior to ureteral stent placement. Patients will be randomized to one of two groups, experimental and placebo. The experimental group will include ureteral stent placement with three peri-ureteral injections of Botox A and fourteen site-specific intradetrusor injections of Botox A. The placebo group will involve a ureteral stent placement with no injection. Based on a randomization sequence from an electronic randomizer, patients will be placed in either Botox injection group or placebo (no injection) group. Patients will be consented at the pre-operative visit, which is usually up to seven days prior to the procedure. After informed consent is obtained, patients will be asked to complete a visual analog pain scale and a ureteral stent symptom questionnaire which can either be turned in during the pre-operative visit or alternatively, if the patient prefers to review the study prior to deciding to participate, can be turned in during the day of stent placement in the pre-operative area at UC Irvine Douglas Hospital before the procedure start time, giving the patient ample time to consider study participation. Baseline post-void residual will also be taken at the pre-operative visit. All stents will be inserted in a retrograde fashion as per standard of care. As standard of care, retrograde contrast injection following the procedure will be done to assess ureteral and renal anatomy. Jaime Landman, MD., and Gamal Ghoniem, MD., will be administering all Botox injections. Three 1mL Botox A injections (10U/mL) will be placed medial, lateral, and inferior to the ureteral orifice. Fourteen 1mL injections (5U/mL) will be placed into the detrusor muscle: three injections at the trigone avoiding the bladder neck, away from the peri-ureteral injections (10U/mL), and eleven injections distributed evenly across the remainder of the bladder. A total of 100 units (1 vial) of Botox A will be used per patient. 100 units of Botox A will be diluted with 10cc's of 0.9% PFNS, 3 cc's will be drawn for the peri-ureteral injections (30 units), then 7 ccs of 0.9% PFNS will be added to the vial to bring to 14cc's. The rest of the Botox A (70u) will be injected into the detrusor muscle.

Procedures will be planned for day surgeries and will be given one pre-operative dose of Kefzol for urinary tract infection prophylaxis as standard of care to all patients. The patient will subsequently be evaluated one hour after the procedure in the recovery room with a visual analog pain scale only. Subsequently, two post-operative evaluations will occur: On the day of stent removal, usually post-operative days (POD) 3 - 9, and POD 14 follow up, The patient will also be assessed during the second follow-up evaluation on POD's 3 - 9 for the possibility of urinary tract infection or urinary retention. A post-void residual will be taken during the 2 week follow-up to assess for urinary retention. On POD 14 visit, a USSQ, medication diary, visual pain analog scale will be collected from the patient. Post-operative evaluation will consist of a visual analog pain scale and a ureteral stent symptom questionnaire (USSQ) to assess pain, lower urinary tract symptoms, and quality of life. In addition, a narcotic diary will be kept by patients to determine the quantity and duration of oral narcotic required during the time the stent is in place. The narcotic diary is important in the study to assess the pain the patient is experiencing in addition to the visual pain analog scale that will be used. A standardized post-operative pain regimen will include Percocet (5mg Oxycodone/325mg Acetominophen) 1 - 2 tablets prn every 4 hours. Pain regimen of Percocet is standard of care and will not be used specifically for research purposes.

Eligibility criteria: Inclusion Criteria:

* Patients requiring unilateral ureteral stent insertion
* Age \> 18
* Renal/ureteral stones (single or multiple)
* Ureteral strictures
* Surveillance ureterscopy
* Willing and able to consent
* Willing and able to complete study questionnaires/diaries
* Willing to use CIC to empty the bladder at any time after study treatment if it is determined to be necessary by the investigator

Exclusion Criteria:

* History of malignancy
* Patients on medical therapy for benign prostatic hyperplasia (alpha blocker and/or 5alpha reductase inhibitor)
* Patients taking muscarinic-receptor antagonists (Ex. detrol, ditropan etc.)
* Patients who have an interstim sacral neuromodulator
* History of urinary retention
* Neurogenic or non-neurogenic detrusor overactivity
* Pregnancy
* Solitary kidney
* Insulin dependent Diabetes Mellitus (Uncontrolled Diabetes (HbA1c \> 8))
* Neuropathy
* History of transplant kidney
* History of narcotic abuse or chronic pain
* Anatomic bladder/ureteral abnormality
* Previous cystectomy/urinary diversion
* Conditions necessitating bilateral ureteral stents
* History of Interstitial cystitis
* Patients with a post-void residual volume of \> 100ml
* Patients with history of urinary retention
* Patients with active urinary tract infection
* Patients with history of chronic urinary tract infections
* Patients with concomitant use of any botulinum toxin within 3 months or any urological use of botulinum toxin in the past
* Patients with active genital infection, other than genital warts, either concurrently or within 4 weeks prior to screening
* Patients with concurrent or previously uninvestigated hematuria within 6 months prior to screening. -Patients with investigated hematuria may have entered the study if urological/renal pathology had been ruled out to the satisfaction of the investigator
* Patients with hemophilia, or other clotting factor deficiencies, or disorders that cause bleeding diathesis Patients with a known allergy or sensitivity to any botulinum toxin preparation (including study medication preparation), anesthetics, or antibiotics used during the study
* Patients with any medical condition that may have put them at increased risk with exposure to Botox including diagnosed myasthenia gravis, Eaton-Lambert syndrome, or amyotrophic lateral sclerosis

Primary outcomes:
measure: Change in Lower Urinary Tract Discomfort between pre-operative visit date and the stent removal date and two week follow up.
timeFrame: At pre-operative visit (average of 7 days before stent placement), stent removal date (3-9 days after stent placement), and 2 week follow up (2 weeks after stent placement)
Secondary outcomes:
measure: Post-operative pain
timeFrame: At pre-operative visit (average of 7 days before stent placement), stent removal date (3-9 days after stent placement), and 2 week follow up (2 weeks after stent placement)
measure: Post-surgical analgesic requirements
timeFrame: post-operative to follow up day (2 weeks)
Other outcomes:
Locations:
city: Orange
country: United States
facility: University of California, Irvine Medical Center
state: California
Study officials:
affiliation: University of California, Irvine Department of Urology
name: Jaime Landman, MD
role: PRINCIPAL_INVESTIGATOR
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