Trial to Visualize the Ureters With Nizaracianine Triflutate in Adults Undergoing Abdominopelvic Surgery

Study Overview
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Brief Summary
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The goal of this clinical trial is to determine if the drug Nizaracianine Triflutate can help surgeons see and avoid the ureters during abdominopelvic surgery. The ureters are thin-wall, collapsible tubes that connect the kidneys to the bladder. They are difficult to see during surgery and are sometimes damaged accidentally. The main questions to answer are: 1) is this drug safe for use in patients undergoing abdominopelvic surgery and 2) can the drug see the ureters while simultaneously providing information about how well they are working. The clinical trial has 3 parts. Surgery patients enrolled in the first part (Phase 2) will receive drug at different doses to determine the best dose. Patients enrolled in the second part (Phase 3A) will be randomly assigned to drug or placebo (sugar), at the best dose from Phase 2, so the two can be compared directly. Patients enrolled in the final part (Phase 3B) will all receive drug at the best dose from Phase 2.

Detailed Description
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Human surgery often suffers from poor visual contrast among anatomical landmarks within the surgical field, and distinguishing one anatomical structure from another becomes nearly impossible if covered by connective tissue, blood, and/or bodily fluids. A major unsolved problem in surgical imaging is anatomical enhancement of the ureters. Damage to the ureters is a serious unintended complication of abdominopelvic and retroperitoneal surgery, with rates as high as 30% in certain gynecological procedures. Ureter damage also leads to extraordinarily high patient morbidity and cost. Currently, to avoid this complication during certain surgeries involving the ureters, much time is taken to define their anatomy using meticulous tissue dissection. Even with such special care, though, approximately 80% of ureteral injuries are only discovered post-operatively when dramatic clinical signs emerge such as rigor, fever, abdominal pain, and/or bacteremia. Ureter injury disproportionally impacts women, not only because of gynecological procedures but some reports have indicated female gender appears to predispose to injury during colectomies. Thus, the lack of availability of a safe diagnostic agent to provide real-time identification of the ureters and assessment of ureter function contributes to the gender disparity that exists within healthcare. Furthermore, patients in non-urban settings may not have access to surgeons with a large surgical volume and thus the years of specialized experience necessary to avoid ureter damage. Surgeon inexperience was identified as a prime risk factor for ureter injury, and teaching hospitals have been implicated in having an increased risk for ureter injury as well. Visual contrast enhancement of the ureters should provide enormous benefit to both patient and surgeon including more rapid initial identification, continuous real-time mapping, reducing or elimination the need for surgical dissection and associated complications in some cases, reducing anesthesia time, and reducing the risk of iatrogenic damage during abdominopelvic procedures across all patient populations. And, if iatrogenic damage still occurs, visual contrast enhancement can quickly identify the site of injury so appropriate repair can be initiated intraoperatively. Nizaracianine Triflutate (ZW800-1) is a novel small molecule drug with a unique zwitterionic chemical structure. This structure prevents the drug from binding non-specifically to tissues and organs after injection and facilitates its excretion by the kidneys into urine. Once in urine, Nizaracianine Triflutate creates visual contrast in the ureters that would otherwise not exist, and using a near-infrared (NIR) camera, surgeons can find the ureters and assess their function in real-time. The clinical trial is divided into three parts: Phase 2 will test 3 different doses of Nizaracianine Triflutate in 12 subjects per dose. Each subject will receive a total of 3 injections of the drug during surgery so that the ureters are visualized throughout. At the end of Phase 2, the best dose for imaging the ureters will be selected. Repeated dose interval will be fixed at 60 min. Dose escalation between cohorts will occur only after a review of safety and tolerability at each dose level including post-operative assessments. Phase 3A will use the best dose from Phase 2 and will randomize 100 subjects total, stratified for re-operative/inflammatory bowel status and BMI, then randomized 1:1 to treatment and control arms, to receive either placebo (sugar) or Nizaracianine Triflutate. Surgeon and subject will be blinded to what is administered. Phase 3B will also use the best dose from Phase 2 and will administer drug to 200 subjects. All subjects will receive the drug and surgeons can administer it up to three times depending on the length of the surgery, with each subject serving as their own control by comparing white light to NIR light. During all three parts of the trial, safety of the drug will be monitored closely. The long-term goal of this Phase 2/Phase 3 clinical trial is to determine whether Nizaracianine Triflutate provides the surgeon with visualization of the ureters throughout surgery, and in so doing can help them lower the risk of injury and improve patient outcome.

Official Title
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Phase 2/3 Randomized Controlled Semi-blinded Trial to Investigate Safety and Effectiveness in Ureter Visualization With Intravenous Nizaracianine Triflutate, in up to 3 Divided Doses, in Adults Undergoing Abdominopelvic Surgery (TRIPHASE)

Conditions
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Injury of Ureter During Surgery (Disorder)

Intervention / Treatment
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* Drug: Nizaracianine Triflutate
* Drug: Placebo Comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old Scheduled to undergo a medically necessary abdominopelvic surgical procedure expected to last ≥ 2 hours (Phase 2) or any duration (Phase 3), during which one or more ureters should be visualized during the procedure. All abdominopelvic surgical procedures are eligible unless specifically excluded in the Exclusion Criteria. For Phase 2, the procedure must require identification of one or both ureters using dissection, mobilization, or other surgical means. The planned surgical procedure is open or minimally invasive surgery (MIS), including robotic. Both ureters are expected to be present and functional. Capable and willing to provide informed consent prior to study-specific procedures Screening laboratory test results are within normal limits, or if any are outside of normal limits, they are considered by the site PI, and confirmed by the lead PI, to be clinically insignificant. Negative pregnancy test in women of childbearing potential Exclusion Criteria: For Phase 2 only, a prior history of abdominopelvic surgery, major abdominopelvic trauma, abdominal or pelvic radiation treatment, intraperitoneal therapy, inflammatory bowel disease, diverticular disease, endometriosis, pelvic inflammatory disease, or peritonitis. Known cardiovascular or pulmonary disease, renal or liver dysfunction, immunological disease, diabetes, or active cancer that would render the study subject unfit for surgery The planned surgical procedure is renal transplant or nephrectomy [note: partial nephrectomy is permitted provided that estimated glomerular filtration rate (eGFR) is not expected to fall below normal age-based limits] Prior renal transplant Impaired renal function defined as an estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73m2 Impaired liver function defined as values > 1.5 times the upper limit of normal (ULN) for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin, or < lower limit of normal (LLN) for albumin Coagulopathy as manifested by international normalized ration (INR) > 1.3 (unless patient is on anti-coagulants) Subjects with a marked baseline prolongation of QT/ corrected QT interval (QTc) interval (e.g., a QTc interval > 480 msec [CTCAE grade 1] using Fridericia's QT correction factor (14) History of a clinically significant allergy or anaphylaxis to a component of the investigational medicinal product (IMP) Known sensitivity to fluorescent light Alcohol or recreational drug use that meets diagnostic and statistical manual of mental disorders (DSM5) criteria for moderate or severe substance use disorder Pregnant or breastfeeding, or lack of effective contraception for at least one week post-surgery in male or female subjects with reproductive potential: for males, condom use; for females, oral contraceptives, diaphragm, or intrauterine devices (IUDs) Any condition that the investigator considers to be potentially jeopardizing to the study subject's well-being or the study's objectives. Participated in an interventional clinical research study within the previous 30 days. The planned use of an 800 nm NIR fluorophore that is not Nizaracianine (e.g., indocyanine green or Pafolacianine) immediately before, during, or immediately after the planned abdominopelvic procedure.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nizaracianine Triflutate Study Drug Arm<br>Participants will receive up to 3 intravenous bolus injections with a minimal interval between doses of 60 minutes (surgeon discretion). Dose will be 1.0, 2.5 or 5.0mg depending on trial phase. | Drug: Nizaracianine Triflutate<br>* Participants will receive up to 3 intravenous bolus injections with a minimal interval between doses of 60 minutes (surgeon discretion). Dose will be 1.0, 2.5 or 5.0mg depending on trial phase.<br>* Other names: ZW800-1;|
| Placebo Comparator: Sugar Comparator Arm<br>In Phase 3A only, 50 subjects will be randomly allocated to receive sugar placebo. | Drug: Placebo Comparator<br>* In Phase 3A only, 50 subjects will be randomly allocated to receive sugar placebo<br>* Other names: Sugar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0 | The occurrence of adverse events (AEs) and serious adverse events (SAEs) related to Nizaracianine following IV administration of Nizaracianine through to follow up visit data (or withdrawal of consent) | From informed consent to final follow up visit (up to 60 days) | 
| Percentage of surgeries in which Nizaracianine improved delineation of ureter anatomy and function compared to standard of care (no drug) | The percentage of surgeons able to successfully identify the ureters at first look (≥ 10 minutes), immediately before and after dissection of the retroperitoneal fascia with NIR light on or off. | 1 day (day of surgery) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nizaracianine Triflutate, ZW800-1, ureter, ureter visualization, abdominopelvic surgery, Near-infrared, fluorescence imaging, TRIPHASE