Paclitaxel (PTX) is an anti-inflammatory and anti-proliferative drug commonly used to prevent arterial restenosis, in the context of urethral stricture there has been investigations using other drugs such as Mitomycin C to prevent urethral restenosis but PTX has not been widely studied for urinary tract. We hypothesized that the delivery of the drug as a coating on the surface of a dilation balloon would allow the medication to have a more uniform delivery and concentric distribution within the tissue achieving lower rates of stricture recurrence by preventing scar tissue growth. The objective of the study was to assess the safety and effectiveness of a drug-coated balloon (DCB) in the treatment of urethral stricture. Endpoints of the study were treatment related serious complications such as urethra rupture or stress urinary incontinence, stricture recurrence at 6 and 12 months, improvement of lower urinary tract symptoms as measured by the IPSS questionnaire, change in the International Index of Erectile Function, repeat treatment rate, change in Qmax, sperm quality, and PTX pharmacokinetics in blood, urine and semen.

We conducted a prospective, non-randomized, open label, multi-center study under a common protocol in Latin America.  The study population was male subjects with a single bulbar urethral stricture that met the inclusion and exclusion criteria. Inclusion criteria were; age ≥ 18 years old, visual confirmation of single urethral stricture less than 2.0 cm with a diameter <12F via cystoscopy or urethrogram, one to three prior diagnosis and treatment of the same stricture (including rigid rod dilation or Direct Vision Internal Urethrotomy (DVIU)) but not prior urethroplasty, significant symptoms of urethral stricture, IPSS score of 13 or higher, Qmax <10 mL/sec.
Fifty-three (53) subjects were enrolled and treated with a PTX DCB during the period November 29, 2016 until September 6, 2017.  
The DCB used was a balloon dilation catheter compatible with 0.038” guide-wires and flexible cystoscopes. The balloon is semi-compliant inflatable balloon that is coated with a proprietary coating containing the active pharmaceutical paclitaxel and the distal end of the catheter has an atraumatic tip. The drug coating covers the working length of the balloon and is evenly distributed across the balloon surface at a concentration of 3.5 µg PTX/mm2. The device has two radiopaque markerbands that indicate the working length of the balloon.
During the treatment procedure all strictures were pre-dilated with a commercially available uncoated balloon or with DVIU. If the pre-dilation increased the stricture diameter by ≥ 50% by visual estimation on retrograde urethrogram, the DCB treatment proceeded.   Otherwise the subject received a second dilation by DVIU prior to DCB treatment. The DCB was advanced over a guide-wire to the portion of the urethra that has a stricture, while the balloon was inflated paclitaxel was transferred off the balloon to the stricture.  The DCB was held at pressure for at least 5 minutes.  After dilation with the DCB a Foley catheter (≤ 14F) was placed for a maximum of 5 days. In this study cohort, 21 subjects participated plasma PTX pharmacokinetics (PK) testing, and all subjects participated in urine and semen PK testing when capable.   
 
Post treatment follow ups were conducted at 5 days, 14 days, 30 days, 90 days, 180 days and 365 days. 42 subjects completed the 365 days follow-up. During the follow up anatomical success was defined as the urethra lumen being greater than 14 Fr caliber.  This was assessed by the passage of a 16 Fr cystoscope, if the urethra lumen appeared narrower than the cystoscope determination was made by attempting to pass a 14 Fr flexible rubber catheter.
Treatment failure was defined by IPSS score of greater than 11 at 90 days follow-up, need for retreatment with a second DCB or if the subject exited the study early with a IPSS greater than 11 at the moment of exit. Stricture recurrence was assessed at 6 months and was defined as (any of the following): urethral lumen <14 Fr, if the subject had a retreatment with DCB, if the subject exited the study early due to treatment failure.

The average age was 50.7 years. A majority of the subjects (83%) were Hispanic or Latino by race, with 15.1%, 1.9% for African and other origin, respectively.  The etiologies of urethral stricture were traumatic (50.9%), iatrogenic (45.3%), and idiopathic (3.8%). The average stricture length was 0.9 cm.  The average number of previous dilation treatments was 1.7.  The average stricture diameter was 2.47 mm.
Average Qmax improved from 5.0 mL/sec (baseline) to 19.5 ml/sec at 12-month follow-up. Average PVR reduced from 141 mL (baseline) to 26.7 mL at 12-month follow-up. 
At 6 months follow-up the overall stricture free rate was 75.5% (37 of 49 subjects were stricture free with 6 subjects that failed urethral lumen test, 4 subjects were retreated with the DCB, and 2 subjects exited the study due to recurrence). At 12 months follow-up the overall stricture free rate was 74.4% (35 of 47 patients were stricture free). The treatment had no significant impact on sexual function as evaluated by IIEF or sperm quality.  Average paclitaxel concentration in subject’s blood plasma was just above the limit of quantification (LOQ = 0.1 ng/mL) at 0.14 ng/mL immediately post procedure and below detectable limits at all timepoints thereafter.  There were no events that met the criteria for unanticipated adverse event, urethra rupture or stress urinary incontinence, no treatment related serious complications during the index procedure and through 12-month follow-up.

Urethral dilation with Drug Coated Balloon is a minimally invasive intervention to treat urethral stricture. It has the advantage of two modes of action: mechanical dilation and paclitaxel drug delivery intended to delay or prevent stricture recurrence.  
Based on published literature, patients with 2, 3, and 4 repeat dilations would be expected to have a stricture recurrence rate of 40%, 20%, and 60% respectively at 12-months . At 12 months post DCB procedure the stricture free rate was 74.4% (35/47) indicating the Paclitaxel DCB performed better than traditional dilation techniques as reported in the literature.  Both Qmax and PVR improved significantly following the DCB procedure demonstrating that subjects were able to void more completely post-treatment.  
Of subjects retreated 4 out of 5 had obliterated or nearly obliterated urethral lumen at baseline and a traumatic etiology (4/5) these factors may have contributed to their stricture recurrence.
The blood paclitaxel concentrations were extremely low immediately post procedure and undetectable 1 hour and longer after procedure indicating little to no systemic drug exposure.

Urethral dilation with paclitaxel drug coated balloon is effective and safe at 12 months follow up, with no observed impact to sexual or reproductive function.

Santucci, R.; Eisenberg, L; Urethrotomy has a Much Lower Success Rate Than Previously Reported; J Urol; May 2010; 183(5):1859-62