<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03229889</url>
  </required_header>
  <id_info>
    <org_study_id>2016-3281</org_study_id>
    <nct_id>NCT03229889</nct_id>
  </id_info>
  <brief_title>Trial of Tadalafil, Tamsulosin and Combination for Access Sheath Deployment</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, Irvine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of California, Irvine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Extensive literature exists on the use of alpha-blocker medications for the removal of kidney&#xD;
      stones. Alpha blockers relax certain muscles and help small blood vessels remain open. They&#xD;
      work by keeping the hormone norepinephrine (noradrenaline) from tightening the muscles in the&#xD;
      walls of smaller arteries and veins, which causes the vessels to remain open and relaxed.&#xD;
      This improves blood flow and lowers blood pressure. There are studies that demonstrate&#xD;
      alpha-blockers decrease ureteral pressure and help the ureter &quot;relax.&quot;&#xD;
&#xD;
      Recent studies have shown that phosphodiesterase inhibitors may also help with ureteral stone&#xD;
      passing. A phosphodiesterase inhibitor is a drug that blocks an enzyme that inhibits&#xD;
      relaxation of smooth muscle. This means that it can help smooth muscle, such as the muscle&#xD;
      that lines the ureter, to relax. While ureteral relaxation is helpful in the passage of&#xD;
      ureteral stones, our study seeks to use this finding by pretreating participants with an&#xD;
      older generation alpha blocker or a phosphodiesterase inhibitor prior to passage of a&#xD;
      ureteral access sheath in cases in which ureteroscopy is being used to approach a ureteral or&#xD;
      renal stone.&#xD;
&#xD;
      By relaxing the ureter, it is possible that a larger access sheath can be safely placed. This&#xD;
      may allow for facilitating passage of the ureteroscope and extraction of stone fragments&#xD;
      while precluding the development of potentially damaging intrarenal pressure from the flow of&#xD;
      irrigant. The ureteral access sheath also protects the ureter from damage during the&#xD;
      procedure. Placement of the largest access sheath possible is helpful in that larger stone&#xD;
      fragments can be retrieved, the flow of irrigant is improved, and the surgical field is kept&#xD;
      clear of blood or debris. To date, nobody has studied whether use of an uro-selective alpha&#xD;
      blocker, alone, or in combination with a 5 phosphodiesterase inhibitor will result in passage&#xD;
      of larger access sheaths.&#xD;
&#xD;
      In this study participants will be randomized into 1 of 4 categories: Flomax (alpha-blocker),&#xD;
      Cialis (5-phosphodiesterase inhibitor), a combination of the 2, or a placebo arm. In this&#xD;
      study the placebo, or no active drug, is the current standard of care and will serve as a&#xD;
      control from the other 3 groups.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Technological improvements such as the miniaturization and development dual lumen&#xD;
      ureteroscopes have improved the urologists' ability to treat urolithiasis1. The quality of&#xD;
      flexible ureterorenoscopy is dependent on adequate visualization of the upper urinary tract.&#xD;
      Adequate irrigation and visualization are compromised by debris from stone fragmentation&#xD;
      and/or any bleeding during treatment. Fortunately, use of an ureteral access sheath (UAS)&#xD;
      increases irrigant flow and reduces intrarenal pressure 2.&#xD;
&#xD;
      Ureteral access sheath technology was significantly improved by a member of our investigative&#xD;
      team (RVC) thereby making it more widely acceptable3-5. The design changes allowed for easier&#xD;
      deployment of the access sheath and the newer design was made to be kink resistant. This&#xD;
      iteration of the device is easily deployed over a guidewire and has varying lengths such that&#xD;
      it can be passed to the level of the stone in each case. Today's ureteral access sheaths&#xD;
      range in size from 11-French to 16-French in diameter. The use of a ureteral access sheath&#xD;
      has been shown to decrease intraoperative time, provide higher stone free rates, incur less&#xD;
      cost due to shorter operating room times, and lead to fewer secondary procedures5,6. The&#xD;
      access sheath should also, in theory, lower the risk of urinary tract infection due to&#xD;
      decreased intrarenal pressure thereby resulting in less pyelovenous and less pyelolymphatic&#xD;
      backflow. Lastly, use of an access sheath minimizes damage to the fragile flexible&#xD;
      ureteroscope and thus increases their longevity while decreasing repair costs7.&#xD;
&#xD;
      Despite the above findings use of the UAS has not been universally embraced. A single study&#xD;
      by Traxer et al., showed the incidence of low grade ureteric injury using UAS was 46% and&#xD;
      that with serious injuries (i.e. urothelial tears) occurred in 13%8. However, a follow-up&#xD;
      study by the same group showed no evidence of delayed long-term ureteral stricture formation;&#xD;
      in fact, the patients who had a ureteral access sheath deployed there was a lower risk of&#xD;
      post-operative complications9. Further, other studies have shown that the rate of ureteral&#xD;
      stricture formation following use of a ureteral access sheath is 1.4% compared to a baseline&#xD;
      rate of 1-3% during routine ureteroscopy without an access sheath10. In the afore cited&#xD;
      study, the solitary occurrence of a post-ureteral access sheath ureteral stricture occurred&#xD;
      at the ureteropelvic junction in a patient who underwent four endoscopic procedures for&#xD;
      struvite stones; in all four surgeries, the access sheath was deployed at the level of iliac&#xD;
      vessels well below the site of the patient's stricture10. Of note, porcine models have shown&#xD;
      decrease ureteral blood flow following the acute deployment of a large access sheath, however&#xD;
      over time the flow normalized and in follow-up there was no increase in post procedural&#xD;
      ureteral stricture formation11.&#xD;
&#xD;
      Most urologists who place a ureteral access sheath do so without any pretreatment for&#xD;
      ureteral relaxation. At our institution, the investigators routinely use alpha blockers&#xD;
      (tamsulosin) as an adjunctive medical therapy to possibly relax the ureteral muscle; the&#xD;
      medication is begun one week prior to surgery as it takes five days for the medicine to reach&#xD;
      a steady state. It has been the investigator's experience that they are able to place larger&#xD;
      ureteral access sheaths (i.e. 14 and 16 French size) with this approach. Additionally,&#xD;
      examination of the ureter at the end of the procedure has shown minimal effect from placement&#xD;
      of the access sheath; to date, the study team has not had any patient return with a post&#xD;
      procedural ureteral stricture. Of note, it is the investigator's practice that if there is&#xD;
      any resistance to deployment of the ureteral access sheath, then a smaller sized sheath is&#xD;
      used; should the smaller sheath encounter resistance to its passage then a ureteral stent is&#xD;
      placed and the procedure is postponed for a week. Stent placement in a ureter facilitates&#xD;
      subsequent placement of an access sheath8,12.&#xD;
&#xD;
      An extensive literature exists on the role of alpha-blocker medications on the relaxation of&#xD;
      ureteral smooth muscle13. This is due to the numerous alpha-1 receptors along the ureter,&#xD;
      particularly in the distal ureter14,15. This knowledge originally led to the development of&#xD;
      medical expulsive therapy in the treatment of ureteral stones. Several meta-analyses have&#xD;
      shown that alpha blockers help passage of distal ureteral stones in the 5-10mm range, in less&#xD;
      time and with less pain. The most extensively studied medication in this regard has been&#xD;
      tamsulosin In addition to alpha blockade, recent in vitro studies have shown that&#xD;
      phosphodiesterase-5 (PDE-5) inhibitors such as a tadalafil, commonly known by its tradename&#xD;
      Cialis, also facilitate ureteral relaxation18-20. This has been substantiated by clinical&#xD;
      studies which showed that sildenafil compared to placebo improved stone passage by 27%21.&#xD;
      Further when tadalafil was added to tamsulosin the result was improved stone passage; the&#xD;
      combined medications were well tolerated22,23.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Enrolling by invitation</last_known_status>
  <start_date type="Actual">June 7, 2017</start_date>
  <completion_date type="Anticipated">April 2022</completion_date>
  <primary_completion_date type="Anticipated">April 2022</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Factorial Assignment</intervention_model>
    <intervention_model_description>Patients will be randomized into 1 of 4 groups: Flomax + Placebo, Cialis + Placebo, Cialis + Flomax, Placebo + Placebo.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Both patients and treating surgeons (who are also on the study team) will be blinded. None physician researchers will be unblinded to tract and randomize patients.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Passage of 16F Access Sheath</measure>
    <time_frame>This will be assessed immediately post-op per patient.</time_frame>
    <description>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 &quot;failure&quot;. 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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Injury</measure>
    <time_frame>This will be assessed immediately post-op per patient.</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complications</measure>
    <time_frame>This will be assessed post-op per patient.</time_frame>
    <description>Intraoperative complications will be recorded as defined by the Clavien-Dindo scale.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>This will be assessed from the first day patients take the drugs until 1 weeks post-op.</time_frame>
    <description>Incidence of adverse events with medications versus placebo as obtained during history on day of surgery, and during follow-up visit 1 week later</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stone-free status</measure>
    <time_frame>This will be assessed immediately post-op as well as 3 months post-op.</time_frame>
    <description>Stone free status as determined by low dose stone protocol CT scan per usual post-operative follow-up.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">220</enrollment>
  <condition>Nephrolithiasis</condition>
  <arm_group>
    <arm_group_label>Flomax + Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cialis + Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cialis + Flomax</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo + Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Given 2 bottles of placebo. They will be instructed to take 1 of each pill for the seven days prior to their surgery.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cialis 5Mg Tablet</intervention_name>
    <description>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.</description>
    <arm_group_label>Cialis + Placebo</arm_group_label>
    <other_name>Tadalafil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Flomax 0.4Mg Capsule</intervention_name>
    <description>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.</description>
    <arm_group_label>Flomax + Placebo</arm_group_label>
    <other_name>Tamsulosin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Combination Product</intervention_type>
    <intervention_name>Cialis + Flomax</intervention_name>
    <description>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.</description>
    <arm_group_label>Cialis + Flomax</arm_group_label>
    <other_name>Tamsulsoin</other_name>
    <other_name>Tadalafil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>This is plant cell based pill that contains no active ingredient. Patients will be asked to 1 pill for 7 days prior to surgery.</description>
    <arm_group_label>Placebo + Placebo</arm_group_label>
    <other_name>Inactive Drug</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients undergoing percutaneous nephrolithotomy (PCNL) or ureteroscopy (URS) for&#xD;
             renal or proximal ureteral urolithiasis&#xD;
&#xD;
          -  A documented sterile urine culture within 1-2 weeks of the procedure&#xD;
&#xD;
          -  ≥ 18 years old&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        - Patients &lt; 18-years-old&#xD;
&#xD;
          -  Presence of ureteral stent or nephrostomy tube prior to scheduled procedure&#xD;
&#xD;
          -  Patients requiring open, endoscopic, or laparoscopic procedure in the same setting as&#xD;
             the intended URS or PCNL&#xD;
&#xD;
          -  Planned concurrent bilateral endoscopic ureteral procedures&#xD;
&#xD;
          -  Patients currently taking alpha-blockers within 14 days of surgery&#xD;
&#xD;
          -  Patients taking PDE-5 inhibitors within 14 days of surgery&#xD;
&#xD;
          -  Pregnant women&#xD;
&#xD;
          -  Active urinary tract infection (UTI) or uncontrolled HIV&#xD;
&#xD;
          -  Uncorrected coagulopathy&#xD;
&#xD;
          -  Patients who cannot stop their blood thinners, and/or non-steroidal anti-inflammatory&#xD;
             medications 5-7 days prior to the procedure&#xD;
&#xD;
          -  Patients allergic to tamsulosin or tadalafil&#xD;
&#xD;
          -  Patients with upcoming cataract surgery due to risk of floppy iris syndrome&#xD;
&#xD;
          -  Patients with history of priapism&#xD;
&#xD;
          -  Patients with hereditary retinitis pigmentosa&#xD;
&#xD;
          -  Patients concurrently using nitrates for myocardial infarction (MI) or angina&#xD;
&#xD;
          -  Patients with high risk cardiovascular disease: left ventricular outflow obstruction,&#xD;
             MI in last 90 days, unstable angina, stroke in last 6 months, uncontrolled arrhythmias&#xD;
&#xD;
          -  Patients with renal impairment (CrCl &lt; 30 mL/min) or severe hepatic impairment&#xD;
             (Child-Pugh score ≥ 10)&#xD;
&#xD;
          -  Patients using CYP3A4 inhibitors such as clarithromycin, ritonavir, ketoconazole, or&#xD;
             Iitraconazole&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jaime Landman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UC Irvin Health</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UC Irvine Health</name>
      <address>
        <city>Orange</city>
        <state>California</state>
        <zip>92868</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Lusch A, Okhunov Z, del Junco M, Yoon R, Khanipour R, Menhadji A, Landman J. Comparison of optics and performance of single channel and a novel dual-channel fiberoptic ureteroscope. Urology. 2015 Jan;85(1):268-72. doi: 10.1016/j.urology.2014.09.032.</citation>
    <PMID>25530400</PMID>
  </reference>
  <reference>
    <citation>Landman J, Venkatesh R, Ragab M, Rehman J, Lee DI, Morrissey KG, Monga M, Sundaram CP. Comparison of intrarenal pressure and irrigant flow during percutaneous nephroscopy with an indwelling ureteral catheter, ureteral occlusion balloon, and ureteral access sheath. Urology. 2002 Oct;60(4):584-7. doi: 10.1016/s0090-4295(02)01861-7.</citation>
    <PMID>12385911</PMID>
  </reference>
  <reference>
    <citation>Takayasu H, Aso Y. Recent development for pyeloureteroscopy: guide tube method for its introduction into the ureter. J Urol. 1974 Aug;112(2):176-8. doi: 10.1016/s0022-5347(17)59675-5. No abstract available.</citation>
    <PMID>4843325</PMID>
  </reference>
  <reference>
    <citation>Monga M, Bhayani S, Landman J, Conradie M, Sundaram CP, Clayman RV. Ureteral access for upper urinary tract disease: the access sheath. J Endourol. 2001 Oct;15(8):831-4. doi: 10.1089/089277901753205843.</citation>
    <PMID>11724124</PMID>
  </reference>
  <reference>
    <citation>Kaplan AG, Lipkin ME, Scales CD Jr, Preminger GM. Use of ureteral access sheaths in ureteroscopy. Nat Rev Urol. 2016 Mar;13(3):135-40. doi: 10.1038/nrurol.2015.271. Epub 2015 Nov 24.</citation>
    <PMID>26597613</PMID>
  </reference>
  <reference>
    <citation>L'esperance JO, Ekeruo WO, Scales CD Jr, Marguet CG, Springhart WP, Maloney ME, Albala DM, Preminger GM. Effect of ureteral access sheath on stone-free rates in patients undergoing ureteroscopic management of renal calculi. Urology. 2005 Aug;66(2):252-5. doi: 10.1016/j.urology.2005.03.019.</citation>
    <PMID>16040093</PMID>
  </reference>
  <reference>
    <citation>Pietrow PK, Auge BK, Delvecchio FC, Silverstein AD, Weizer AZ, Albala DM, Preminger GM. Techniques to maximize flexible ureteroscope longevity. Urology. 2002 Nov;60(5):784-8. doi: 10.1016/s0090-4295(02)01948-9.</citation>
    <PMID>12429296</PMID>
  </reference>
  <reference>
    <citation>Traxer O, Thomas A. Prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. J Urol. 2013 Feb;189(2):580-4. doi: 10.1016/j.juro.2012.08.197. Epub 2012 Oct 8.</citation>
    <PMID>22982421</PMID>
  </reference>
  <reference>
    <citation>Traxer O, Wendt-Nordahl G, Sodha H, Rassweiler J, Meretyk S, Tefekli A, Coz F, de la Rosette JJ. Differences in renal stone treatment and outcomes for patients treated either with or without the support of a ureteral access sheath: The Clinical Research Office of the Endourological Society Ureteroscopy Global Study. World J Urol. 2015 Dec;33(12):2137-44. doi: 10.1007/s00345-015-1582-8. Epub 2015 May 14.</citation>
    <PMID>25971204</PMID>
  </reference>
  <reference>
    <citation>Delvecchio FC, Auge BK, Brizuela RM, Weizer AZ, Silverstein AD, Lallas CD, Pietrow PK, Albala DM, Preminger GM. Assessment of stricture formation with the ureteral access sheath. Urology. 2003 Mar;61(3):518-22; discussion 522. doi: 10.1016/s0090-4295(02)02433-0.</citation>
    <PMID>12639636</PMID>
  </reference>
  <reference>
    <citation>Lallas CD, Auge BK, Raj GV, Santa-Cruz R, Madden JF, Preminger GM. Laser Doppler flowmetric determination of ureteral blood flow after ureteral access sheath placement. J Endourol. 2002 Oct;16(8):583-90. doi: 10.1089/089277902320913288.</citation>
    <PMID>12470467</PMID>
  </reference>
  <reference>
    <citation>Miernik A, Wilhelm K, Ardelt PU, Adams F, Kuehhas FE, Schoenthaler M. Standardized flexible ureteroscopic technique to improve stone-free rates. Urology. 2012 Dec;80(6):1198-202. doi: 10.1016/j.urology.2012.08.042.</citation>
    <PMID>23206763</PMID>
  </reference>
  <reference>
    <citation>Hollingsworth JM, Rogers MA, Kaufman SR, Bradford TJ, Saint S, Wei JT, Hollenbeck BK. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet. 2006 Sep 30;368(9542):1171-9. doi: 10.1016/S0140-6736(06)69474-9.</citation>
    <PMID>17011944</PMID>
  </reference>
  <reference>
    <citation>Edyvane KA, Trussell DC, Jonavicius J, Henwood A, Marshall VR. Presence and regional variation in peptide-containing nerves in the human ureter. J Auton Nerv Syst. 1992 Jun 15;39(2):127-37. doi: 10.1016/0165-1838(92)90053-j.</citation>
    <PMID>1385511</PMID>
  </reference>
  <reference>
    <citation>Itoh Y, Kojima Y, Yasui T, Tozawa K, Sasaki S, Kohri K. Examination of alpha 1 adrenoceptor subtypes in the human ureter. Int J Urol. 2007 Aug;14(8):749-53. doi: 10.1111/j.1442-2042.2007.01812.x.</citation>
    <PMID>17681068</PMID>
  </reference>
  <reference>
    <citation>Davenport K, Timoney AG, Keeley FX Jr. Effect of smooth muscle relaxant drugs on proximal human ureteric activity in vivo: a pilot study. Urol Res. 2007 Aug;35(4):207-13. doi: 10.1007/s00240-007-0100-x. Epub 2007 May 26.</citation>
    <PMID>17530238</PMID>
  </reference>
  <reference>
    <citation>Kobayashi S, Tomiyama Y, Hoyano Y, Yamazaki Y, Kusama H, Itoh Y, Kubota Y, Kohri K. Gene expressions and mechanical functions of alpha1-adrenoceptor subtypes in mouse ureter. World J Urol. 2009 Dec;27(6):775-80. doi: 10.1007/s00345-009-0396-y.</citation>
    <PMID>19259685</PMID>
  </reference>
  <reference>
    <citation>Taher A, Schulz-Knappe P, Meyer M, Truss M, Forssmann WG, Stief CG, Jonas U. Characterization of cyclic nucleotide phosphodiesterase isoenzymes in the human ureter and their functional role in vitro. World J Urol. 1994;12(5):286-91. doi: 10.1007/BF00191209.</citation>
    <PMID>7866426</PMID>
  </reference>
  <reference>
    <citation>Kuhn R, Uckert S, Stief CG, Truss MC, Lietz B, Bischoff E, Schramm M, Jonas U. Relaxation of human ureteral smooth muscle in vitro by modulation of cyclic nucleotide-dependent pathways. Urol Res. 2000 Apr;28(2):110-5. doi: 10.1007/s002400050147.</citation>
    <PMID>10850633</PMID>
  </reference>
  <reference>
    <citation>Gratzke C, Uckert S, Kedia G, Reich O, Schlenker B, Seitz M, Becker AJ, Stief CG. In vitro effects of PDE5 inhibitors sildenafil, vardenafil and tadalafil on isolated human ureteral smooth muscle: a basic research approach. Urol Res. 2007 Feb;35(1):49-54. doi: 10.1007/s00240-006-0073-1. Epub 2006 Nov 11.</citation>
    <PMID>17102958</PMID>
  </reference>
  <reference>
    <citation>Shokeir AA, Tharwat MA, Abolazm AE, Harraz A. Sildenafil citrate as a medical expulsive therapy for distal ureteric stones: A randomised double-blind placebo-controlled study. Arab J Urol. 2016 Mar;14(1):1-6. doi: 10.1016/j.aju.2015.12.001. Epub 2016 Jan 21.</citation>
    <PMID>26966585</PMID>
  </reference>
  <reference>
    <citation>Jayant K, Agrawal R, Agrawal S. Tamsulosin versus tamsulosin plus tadalafil as medical expulsive therapy for lower ureteric stones: a randomized controlled trial. Int J Urol. 2014 Oct;21(10):1012-5. doi: 10.1111/iju.12496. Epub 2014 Jun 3.</citation>
    <PMID>24894533</PMID>
  </reference>
  <reference>
    <citation>Kloner RA, Jackson G, Emmick JT, Mitchell MI, Bedding A, Warner MR, Pereira A. Interaction between the phosphodiesterase 5 inhibitor, tadalafil and 2 alpha-blockers, doxazosin and tamsulosin in healthy normotensive men. J Urol. 2004 Nov;172(5 Pt 1):1935-40. doi: 10.1097/01.ju.0000142687.75577.e4.</citation>
    <PMID>15540759</PMID>
  </reference>
  <reference>
    <citation>Schoenthaler M, Buchholz N, Farin E, Ather H, Bach C, Bach T, Denstedt JD, Fritsche HM, Grasso M, Hakenberg OW, Herwig R, Knoll T, Kuehhas FE, Liatsikos E, Liske P, Marberger M, Osther PJ, Santos JM, Sarica K, Seitz C, Straub M, Traxer O, Trinchieri A, Turney B, Miernik A. The Post-Ureteroscopic Lesion Scale (PULS): a multicenter video-based evaluation of inter-rater reliability. World J Urol. 2014 Aug;32(4):1033-40. doi: 10.1007/s00345-013-1185-1. Epub 2013 Oct 18.</citation>
    <PMID>24135917</PMID>
  </reference>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>June 26, 2017</study_first_submitted>
  <study_first_submitted_qc>July 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 26, 2017</study_first_posted>
  <last_update_submitted>April 15, 2021</last_update_submitted>
  <last_update_submitted_qc>April 15, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 19, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Access Sheath</keyword>
  <keyword>PCNL</keyword>
  <keyword>Percutaneous Nephrolithotomy</keyword>
  <keyword>Ureteroscopy</keyword>
  <keyword>Alpha Blocker</keyword>
  <keyword>Flomax</keyword>
  <keyword>PDE-5 Inhibitor</keyword>
  <keyword>Cialis</keyword>
  <keyword>Phosphodiesterase Inhibitor</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nephrolithiasis</mesh_term>
    <mesh_term>Kidney Calculi</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tadalafil</mesh_term>
    <mesh_term>Tamsulosin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03229889
org study id: 2016-3281
nct id: NCT03229889
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
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.
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.
allocation: Randomized
intervention model: Factorial Assignment
intervention model description: Patients will be randomized into 1 of 4 groups: Flomax + Placebo, Cialis + Placebo, Cialis + Flomax, Placebo + Placebo.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: Both patients and treating surgeons (who are also on the study team) will be blinded. None physician researchers will be unblinded to tract and randomize patients.
measure: Passage of 16F Access Sheath
time frame: This will be assessed immediately post-op per patient.
description: 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.
measure: Injury
time frame: This will be assessed immediately post-op per patient.
description: 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
measure: Complications
time frame: This will be assessed post-op per patient.
description: Intraoperative complications will be recorded as defined by the Clavien-Dindo scale.
measure: Adverse events
time frame: This will be assessed from the first day patients take the drugs until 1 weeks post-op.
description: Incidence of adverse events with medications versus placebo as obtained during history on day of surgery, and during follow-up visit 1 week later
measure: Stone-free status
time frame: This will be assessed immediately post-op as well as 3 months post-op.
description: Stone free status as determined by low dose stone protocol CT scan per usual post-operative follow-up.
arm group label: Flomax + Placebo
arm group type: Active Comparator
description: 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.
arm group label: Cialis + Placebo
arm group type: Active Comparator
description: 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.
arm group label: Cialis + Flomax
arm group type: Active Comparator
description: 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.
arm group label: Placebo + Placebo
arm group type: Placebo Comparator
description: Given 2 bottles of placebo. They will be instructed to take 1 of each pill for the seven days prior to their surgery.
intervention type: Drug
intervention name: Cialis 5Mg Tablet
description: 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.
arm group label: Cialis + Placebo
other name: Tadalafil
intervention type: Drug
intervention name: Flomax 0.4Mg Capsule
description: 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.
arm group label: Flomax + Placebo
other name: Tamsulosin
intervention type: Combination Product
intervention name: Cialis + Flomax
description: 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.
arm group label: Cialis + Flomax
other name: Tamsulsoin
other name: Tadalafil
intervention type: Drug
intervention name: Placebo
description: This is plant cell based pill that contains no active ingredient. Patients will be asked to 1 pill for 7 days prior to surgery.
arm group label: Placebo + Placebo
other name: Inactive Drug
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Jaime Landman, MD
role: Principal Investigator
affiliation: UC Irvin Health
facility: 
country: United States
citation: Lusch A, Okhunov Z, del Junco M, Yoon R, Khanipour R, Menhadji A, Landman J. Comparison of optics and performance of single channel and a novel dual-channel fiberoptic ureteroscope. Urology. 2015 Jan;85(1):268-72. doi: 10.1016/j.urology.2014.09.032.
PMID: 25530400
citation: Landman J, Venkatesh R, Ragab M, Rehman J, Lee DI, Morrissey KG, Monga M, Sundaram CP. Comparison of intrarenal pressure and irrigant flow during percutaneous nephroscopy with an indwelling ureteral catheter, ureteral occlusion balloon, and ureteral access sheath. Urology. 2002 Oct;60(4):584-7. doi: 10.1016/s0090-4295(02)01861-7.
PMID: 12385911
citation: Takayasu H, Aso Y. Recent development for pyeloureteroscopy: guide tube method for its introduction into the ureter. J Urol. 1974 Aug;112(2):176-8. doi: 10.1016/s0022-5347(17)59675-5. No abstract available.
PMID: 4843325
citation: Monga M, Bhayani S, Landman J, Conradie M, Sundaram CP, Clayman RV. Ureteral access for upper urinary tract disease: the access sheath. J Endourol. 2001 Oct;15(8):831-4. doi: 10.1089/089277901753205843.
PMID: 11724124
citation: Kaplan AG, Lipkin ME, Scales CD Jr, Preminger GM. Use of ureteral access sheaths in ureteroscopy. Nat Rev Urol. 2016 Mar;13(3):135-40. doi: 10.1038/nrurol.2015.271. Epub 2015 Nov 24.
PMID: 26597613
citation: L'esperance JO, Ekeruo WO, Scales CD Jr, Marguet CG, Springhart WP, Maloney ME, Albala DM, Preminger GM. Effect of ureteral access sheath on stone-free rates in patients undergoing ureteroscopic management of renal calculi. Urology. 2005 Aug;66(2):252-5. doi: 10.1016/j.urology.2005.03.019.
PMID: 16040093
citation: Pietrow PK, Auge BK, Delvecchio FC, Silverstein AD, Weizer AZ, Albala DM, Preminger GM. Techniques to maximize flexible ureteroscope longevity. Urology. 2002 Nov;60(5):784-8. doi: 10.1016/s0090-4295(02)01948-9.
PMID: 12429296
citation: Traxer O, Thomas A. Prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. J Urol. 2013 Feb;189(2):580-4. doi: 10.1016/j.juro.2012.08.197. Epub 2012 Oct 8.
PMID: 22982421
citation: Traxer O, Wendt-Nordahl G, Sodha H, Rassweiler J, Meretyk S, Tefekli A, Coz F, de la Rosette JJ. Differences in renal stone treatment and outcomes for patients treated either with or without the support of a ureteral access sheath: The Clinical Research Office of the Endourological Society Ureteroscopy Global Study. World J Urol. 2015 Dec;33(12):2137-44. doi: 10.1007/s00345-015-1582-8. Epub 2015 May 14.
PMID: 25971204
citation: Delvecchio FC, Auge BK, Brizuela RM, Weizer AZ, Silverstein AD, Lallas CD, Pietrow PK, Albala DM, Preminger GM. Assessment of stricture formation with the ureteral access sheath. Urology. 2003 Mar;61(3):518-22; discussion 522. doi: 10.1016/s0090-4295(02)02433-0.
PMID: 12639636
citation: Lallas CD, Auge BK, Raj GV, Santa-Cruz R, Madden JF, Preminger GM. Laser Doppler flowmetric determination of ureteral blood flow after ureteral access sheath placement. J Endourol. 2002 Oct;16(8):583-90. doi: 10.1089/089277902320913288.
PMID: 12470467
citation: Miernik A, Wilhelm K, Ardelt PU, Adams F, Kuehhas FE, Schoenthaler M. Standardized flexible ureteroscopic technique to improve stone-free rates. Urology. 2012 Dec;80(6):1198-202. doi: 10.1016/j.urology.2012.08.042.
PMID: 23206763
citation: Hollingsworth JM, Rogers MA, Kaufman SR, Bradford TJ, Saint S, Wei JT, Hollenbeck BK. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet. 2006 Sep 30;368(9542):1171-9. doi: 10.1016/S0140-6736(06)69474-9.
PMID: 17011944
citation: Edyvane KA, Trussell DC, Jonavicius J, Henwood A, Marshall VR. Presence and regional variation in peptide-containing nerves in the human ureter. J Auton Nerv Syst. 1992 Jun 15;39(2):127-37. doi: 10.1016/0165-1838(92)90053-j.
PMID: 1385511
citation: Itoh Y, Kojima Y, Yasui T, Tozawa K, Sasaki S, Kohri K. Examination of alpha 1 adrenoceptor subtypes in the human ureter. Int J Urol. 2007 Aug;14(8):749-53. doi: 10.1111/j.1442-2042.2007.01812.x.
PMID: 17681068
citation: Davenport K, Timoney AG, Keeley FX Jr. Effect of smooth muscle relaxant drugs on proximal human ureteric activity in vivo: a pilot study. Urol Res. 2007 Aug;35(4):207-13. doi: 10.1007/s00240-007-0100-x. Epub 2007 May 26.
PMID: 17530238
citation: Kobayashi S, Tomiyama Y, Hoyano Y, Yamazaki Y, Kusama H, Itoh Y, Kubota Y, Kohri K. Gene expressions and mechanical functions of alpha1-adrenoceptor subtypes in mouse ureter. World J Urol. 2009 Dec;27(6):775-80. doi: 10.1007/s00345-009-0396-y.
PMID: 19259685
citation: Taher A, Schulz-Knappe P, Meyer M, Truss M, Forssmann WG, Stief CG, Jonas U. Characterization of cyclic nucleotide phosphodiesterase isoenzymes in the human ureter and their functional role in vitro. World J Urol. 1994;12(5):286-91. doi: 10.1007/BF00191209.
PMID: 7866426
citation: Kuhn R, Uckert S, Stief CG, Truss MC, Lietz B, Bischoff E, Schramm M, Jonas U. Relaxation of human ureteral smooth muscle in vitro by modulation of cyclic nucleotide-dependent pathways. Urol Res. 2000 Apr;28(2):110-5. doi: 10.1007/s002400050147.
PMID: 10850633
citation: Gratzke C, Uckert S, Kedia G, Reich O, Schlenker B, Seitz M, Becker AJ, Stief CG. In vitro effects of PDE5 inhibitors sildenafil, vardenafil and tadalafil on isolated human ureteral smooth muscle: a basic research approach. Urol Res. 2007 Feb;35(1):49-54. doi: 10.1007/s00240-006-0073-1. Epub 2006 Nov 11.
PMID: 17102958
citation: Shokeir AA, Tharwat MA, Abolazm AE, Harraz A. Sildenafil citrate as a medical expulsive therapy for distal ureteric stones: A randomised double-blind placebo-controlled study. Arab J Urol. 2016 Mar;14(1):1-6. doi: 10.1016/j.aju.2015.12.001. Epub 2016 Jan 21.
PMID: 26966585
citation: Jayant K, Agrawal R, Agrawal S. Tamsulosin versus tamsulosin plus tadalafil as medical expulsive therapy for lower ureteric stones: a randomized controlled trial. Int J Urol. 2014 Oct;21(10):1012-5. doi: 10.1111/iju.12496. Epub 2014 Jun 3.
PMID: 24894533
citation: Kloner RA, Jackson G, Emmick JT, Mitchell MI, Bedding A, Warner MR, Pereira A. Interaction between the phosphodiesterase 5 inhibitor, tadalafil and 2 alpha-blockers, doxazosin and tamsulosin in healthy normotensive men. J Urol. 2004 Nov;172(5 Pt 1):1935-40. doi: 10.1097/01.ju.0000142687.75577.e4.
PMID: 15540759
citation: Schoenthaler M, Buchholz N, Farin E, Ather H, Bach C, Bach T, Denstedt JD, Fritsche HM, Grasso M, Hakenberg OW, Herwig R, Knoll T, Kuehhas FE, Liatsikos E, Liske P, Marberger M, Osther PJ, Santos JM, Sarica K, Seitz C, Straub M, Traxer O, Trinchieri A, Turney B, Miernik A. The Post-Ureteroscopic Lesion Scale (PULS): a multicenter video-based evaluation of inter-rater reliability. World J Urol. 2014 Aug;32(4):1033-40. doi: 10.1007/s00345-013-1185-1. Epub 2013 Oct 18.
PMID: 24135917
responsible party type: Sponsor
mesh term: Nephrolithiasis
mesh term: Kidney Calculi
mesh term: Tadalafil
mesh term: Tamsulosin
sharing ipd: Undecided