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

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 originally planned to test 3 different doses of Nizaracianine Triflutate in 12 subjects per dose. The planned Phase 2 cohort 3 (5 mg per dose x3 for a total of 15 mg) was removed in the current version of the protocol as available results from the 1 mg cohort and 2.5 mg cohort indicated that the ureters could be readily visualized and there was an anticipated high risk of NIR camera saturation with the 5 mg dose. The Lead PI determined that there was no scientific or clinical justification to escalate to a 5 mg dose in the Phase 2 portion of the study. Each of the subjects in the other 2 cohorts received a total of 3 injections of the drug during surgery so that the ureters were visualized throughout. At the end of Phase 2, the best dose for imaging the ureters was selected as 2.5mg Nizaracianine Trifluatate.

Phase 3A will use 2.5mg Nizaracianine Trifluatate 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 2.5mg Nizaracianine Trifluatate 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.

• The fraction of cases in which ureter identification did not require invasive procedures or dissection of surrounding tissue [Срок оценки: 1 day (day of surgery)]
• Average time required for initial ureter identification (minutes) [Срок оценки: 1 day (day of surgery)]
• Fraction of cases for which ureter integrity status (leak vs. no leak) and function (flow/obstructions) were determined at closing without the need for invasive procedures and/or tissue manipulation [Срок оценки: 1 day (day of surgery)]
• Among cases that normally require ureter skeletonization/ureter dissection, the proportion of cases where skeletonization/ureter dissection could be reduced or eliminated [Срок оценки: 1 day (day of surgery)]
• Average time period of ureter visualization provided by the first dose of Nizaracianine [Срок оценки: 1 day (day of surgery)]
• Average dose interval and average number of doses of Nizaracianine preferred by surgeons for optimal visualization of the ureters during surgeries of various lengths (Phase 3 only) [Срок оценки: 1 day (day of surgery)]
• Among subjects with ureter injury, the proportion of cases detected intraoperatively [Срок оценки: 1 day (day of surgery)]
• Among subjects with intraoperative detection of ureter injury, the proportion of cases in which Nizaracianine assisted repair [Срок оценки: 1 day (day of surgery)]
• For a particular surgical procedure type, average overall surgery time (Phase 3A only) [Срок оценки: 1 day (day of surgery)]