Trial of Tadalafil, Tamsulosin and Combination for Access Sheath Deployment

Study Overview
=================
Brief Summary
-----------------
Extensive literature exists on the use of alpha-blocker medications for the removal of kidney stones. Alpha blockers relax certain muscles and help small blood vessels remain open. They work by keeping the hormone norepinephrine (noradrenaline) from tightening the muscles in the walls of smaller arteries and veins, which causes the vessels to remain open and relaxed. This improves blood flow and lowers blood pressure. There are studies that demonstrate alpha-blockers decrease ureteral pressure and help the ureter relax. Recent studies have shown that phosphodiesterase inhibitors may also help with ureteral stone passing. A phosphodiesterase inhibitor is a drug that blocks an enzyme that inhibits relaxation of smooth muscle. This means that it can help smooth muscle, such as the muscle that lines the ureter, to relax. While ureteral relaxation is helpful in the passage of ureteral stones, our study seeks to use this finding by pretreating participants with an older generation alpha blocker or a phosphodiesterase inhibitor prior to passage of a ureteral access sheath in cases in which ureteroscopy is being used to approach a ureteral or renal stone. By relaxing the ureter, it is possible that a larger access sheath can be safely placed. This may allow for facilitating passage of the ureteroscope and extraction of stone fragments while precluding the development of potentially damaging intrarenal pressure from the flow of irrigant. The ureteral access sheath also protects the ureter from damage during the procedure. Placement of the largest access sheath possible is helpful in that larger stone fragments can be retrieved, the flow of irrigant is improved, and the surgical field is kept clear of blood or debris. To date, nobody has studied whether use of an uro-selective alpha blocker, alone, or in combination with a 5 phosphodiesterase inhibitor will result in passage of larger access sheaths. In this study participants will be randomized into 1 of 4 categories: Flomax (alpha-blocker), Cialis (5-phosphodiesterase inhibitor), a combination of the 2, or a placebo arm. In this study the placebo, or no active drug, is the current standard of care and will serve as a control from the other 3 groups.

Detailed Description
-----------------
Technological improvements such as the miniaturization and development dual lumen ureteroscopes have improved the urologists' ability to treat urolithiasis1. The quality of flexible ureterorenoscopy is dependent on adequate visualization of the upper urinary tract. Adequate irrigation and visualization are compromised by debris from stone fragmentation and/or any bleeding during treatment. Fortunately, use of an ureteral access sheath (UAS) increases irrigant flow and reduces intrarenal pressure 2. Ureteral access sheath technology was significantly improved by a member of our investigative team (RVC) thereby making it more widely acceptable3-5. The design changes allowed for easier deployment of the access sheath and the newer design was made to be kink resistant. This iteration of the device is easily deployed over a guidewire and has varying lengths such that it can be passed to the level of the stone in each case. Today's ureteral access sheaths range in size from 11-French to 16-French in diameter. The use of a ureteral access sheath has been shown to decrease intraoperative time, provide higher stone free rates, incur less cost due to shorter operating room times, and lead to fewer secondary procedures5,6. The access sheath should also, in theory, lower the risk of urinary tract infection due to decreased intrarenal pressure thereby resulting in less pyelovenous and less pyelolymphatic backflow. Lastly, use of an access sheath minimizes damage to the fragile flexible ureteroscope and thus increases their longevity while decreasing repair costs7. Despite the above findings use of the UAS has not been universally embraced. A single study by Traxer et al., showed the incidence of low grade ureteric injury using UAS was 46% and that with serious injuries (i.e. urothelial tears) occurred in 13%8. However, a follow-up study by the same group showed no evidence of delayed long-term ureteral stricture formation; in fact, the patients who had a ureteral access sheath deployed there was a lower risk of post-operative complications9. Further, other studies have shown that the rate of ureteral stricture formation following use of a ureteral access sheath is 1.4% compared to a baseline rate of 1-3% during routine ureteroscopy without an access sheath10. In the afore cited study, the solitary occurrence of a post-ureteral access sheath ureteral stricture occurred at the ureteropelvic junction in a patient who underwent four endoscopic procedures for struvite stones; in all four surgeries, the access sheath was deployed at the level of iliac vessels well below the site of the patient's stricture10. Of note, porcine models have shown decrease ureteral blood flow following the acute deployment of a large access sheath, however over time the flow normalized and in follow-up there was no increase in post procedural ureteral stricture formation11. Most urologists who place a ureteral access sheath do so without any pretreatment for ureteral relaxation. At our institution, the investigators routinely use alpha blockers (tamsulosin) as an adjunctive medical therapy to possibly relax the ureteral muscle; the medication is begun one week prior to surgery as it takes five days for the medicine to reach a steady state. It has been the investigator's experience that they are able to place larger ureteral access sheaths (i.e. 14 and 16 French size) with this approach. Additionally, examination of the ureter at the end of the procedure has shown minimal effect from placement of the access sheath; to date, the study team has not had any patient return with a post procedural ureteral stricture. Of note, it is the investigator's practice that if there is any resistance to deployment of the ureteral access sheath, then a smaller sized sheath is used; should the smaller sheath encounter resistance to its passage then a ureteral stent is placed and the procedure is postponed for a week. Stent placement in a ureter facilitates subsequent placement of an access sheath8,12. An extensive literature exists on the role of alpha-blocker medications on the relaxation of ureteral smooth muscle13. This is due to the numerous alpha-1 receptors along the ureter, particularly in the distal ureter14,15. This knowledge originally led to the development of medical expulsive therapy in the treatment of ureteral stones. Several meta-analyses have shown that alpha blockers help passage of distal ureteral stones in the 5-10mm range, in less time and with less pain. The most extensively studied medication in this regard has been tamsulosin In addition to alpha blockade, recent in vitro studies have shown that phosphodiesterase-5 (PDE-5) inhibitors such as a tadalafil, commonly known by its tradename Cialis, also facilitate ureteral relaxation18-20. This has been substantiated by clinical studies which showed that sildenafil compared to placebo improved stone passage by 27%21. Further when tadalafil was added to tamsulosin the result was improved stone passage; the combined medications were well tolerated22,23.

Official Title
-----------------
Medication Facilitated Ureteral Access Sheath Deployment During Ureteroscopy and Endoscopic-Guided Percutaneous Nephrolithotomy: A Randomized Double-Blind Placebo Controlled Trial of Tadalafil, Tamsulosin and Combination

Conditions
-----------------
Nephrolithiasis

Intervention / Treatment
-----------------
* Drug: Cialis 5Mg Tablet
* Drug: Flomax 0.4Mg Capsule
* Combination Product: Cialis + Flomax
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients undergoing percutaneous nephrolithotomy (PCNL) or ureteroscopy (URS) for renal or proximal ureteral urolithiasis A documented sterile urine culture within 1-2 weeks of the procedure ≥ 18 years old Ability to understand and the willingness to sign a written informed consent Exclusion Criteria: - Patients < 18-years-old Presence of ureteral stent or nephrostomy tube prior to scheduled procedure Patients requiring open, endoscopic, or laparoscopic procedure in the same setting as the intended URS or PCNL Planned concurrent bilateral endoscopic ureteral procedures Patients currently taking alpha-blockers within 14 days of surgery Patients taking PDE-5 inhibitors within 14 days of surgery Pregnant women Active urinary tract infection (UTI) or uncontrolled HIV Uncorrected coagulopathy Patients who cannot stop their blood thinners, and/or non-steroidal anti-inflammatory medications 5-7 days prior to the procedure Patients allergic to tamsulosin or tadalafil Patients with upcoming cataract surgery due to risk of floppy iris syndrome Patients with history of priapism Patients with hereditary retinitis pigmentosa Patients concurrently using nitrates for myocardial infarction (MI) or angina Patients with high risk cardiovascular disease: left ventricular outflow obstruction, MI in last 90 days, unstable angina, stroke in last 6 months, uncontrolled arrhythmias Patients with renal impairment (CrCl < 30 mL/min) or severe hepatic impairment (Child-Pugh score ≥ 10) Patients using CYP3A4 inhibitors such as clarithromycin, ritonavir, ketoconazole, or Iitraconazole

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Patients will be randomized into 1 of 4 groups: Flomax + Placebo, Cialis + Placebo, Cialis + Flomax, Placebo + Placebo.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Flomax + Placebo<br>Patients will be prescribed Flomax 0.4Mg Capsule and given a bottle of placebo. They will be instructed to take 1 of each pill for the seven days prior to their surgery. | Drug: Flomax 0.4Mg Capsule<br>* Tamsulosin is an alpha-blocker that has been shown to relax smooth muscle in the genitourinary system. Patients will be asked to 1 pill for 7 days prior to surgery.<br>* Other names: Tamsulosin;|
| Active Comparator: Cialis + Placebo<br>Patients will be prescribed Cialis 5Mg tablet and given a bottle of placebo. They will be instructed to take 1 of each pill for the seven days prior to their surgery. | Drug: Cialis 5Mg Tablet<br>* Cialis is a PDE-5 inhibitor that has been shown to relax smooth muscle. Patients will be asked to 1 pill for 7 days prior to surgery.<br>* Other names: Tadalafil;|
| Active Comparator: Cialis + Flomax<br>Patients will be prescribed .4mg of Flomax and 5mg of Cialis. They will be instructed to take 1 of each pill for the seven days prior to their surgery. | Combination Product: Cialis + Flomax<br>* Cialis is a PDE-5 inhibitor that has been shown to relax smooth muscle. Tamsulosin is an alpha-blocker that has been shown to relax smooth muscle in the genitourinary system. A combination of these two drugs may increase the relaxation effects in the ureter. Patients will be asked to 1 of each pill for 7 days prior to surgery.<br>* Other names: Tadalafil;|
| Placebo Comparator: Placebo + Placebo<br>Given 2 bottles of placebo. They will be instructed to take 1 of each pill for the seven days prior to their surgery. | Drug: Placebo<br>* This is plant cell based pill that contains no active ingredient. Patients will be asked to 1 pill for 7 days prior to surgery.<br>* Other names: Inactive Drug;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Passage of 16F Access Sheath | Our primary objective is to assess the ability of a uroselective alpha-blocker (tamsulosin) and PDE-5 inhibitor (tadalafil), either alone or in combination will facilitate the passage of a 16F ureteral access sheath. Successful deployment will be defined as passage of the 16F ureteral access sheath into the proximal ureter or ureteropelvic junction. Difficulty in passing a 16F ureteral access sheath will be defined as a failure. In this situation, we will place smaller ureteral access sheath (i.e. 11F or 14F), or opt to place a stent to dilate the ureter, and plan for surgery in the future; this is standard of care. | This will be assessed immediately post-op per patient. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Injury | Assessment of ureteral wall injury as defined by the post-ureteroscopic lesion score (PULS) as recorded during removal of the access sheath at the end of the surgical procedure | This will be assessed immediately post-op per patient. | 
| Complications | Intraoperative complications will be recorded as defined by the Clavien-Dindo scale. | This will be assessed post-op per patient. | 
| Adverse events | Incidence of adverse events with medications versus placebo as obtained during history on day of surgery, and during follow-up visit 1 week later | This will be assessed from the first day patients take the drugs until 1 weeks post-op. | 
| Stone-free status | Stone free status as determined by low dose stone protocol CT scan per usual post-operative follow-up. | This will be assessed immediately post-op as well as 3 months post-op. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Access Sheath, PCNL, Percutaneous Nephrolithotomy, Ureteroscopy, Alpha Blocker, Flomax, PDE-5 Inhibitor, Cialis, Phosphodiesterase Inhibitor