Clinical trial NCT06101745: Trial to Visualize the Ureters With Nizaracianine Triflutate in Adults Undergoing Abdominopelvic Surgery
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Injury of Ureter During Surgery (Disorder)
Keywords: Nizaracianine Triflutate
ZW800-1
ureter
ureter visualization
abdominopelvic surgery
Near-infrared
fluorescence imaging
TRIPHASE
Lead sponsor: Curadel Surgical Innovations, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Leiden University Medical Center
name: Erasmus Medical Center
name: University of Massachusetts Chan Medical School, Worcester
name: Stanford University
name: Cedars-Sinai Medical Center
First posted: 2023-10-26
Enrollment: 336
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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:

* 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.

Primary outcomes:
measure: The fraction of subjects for whom the surgeon is able to successfully identify the required length of the ureters (specified prior to surgery by the surgeon), as verified by three independent blinded reviewers
timeFrame: 1 day (day of surgery)
Secondary outcomes:
measure: The fraction of cases in which ureter identification did not require invasive procedures or dissection of surrounding tissue
timeFrame: 1 day (day of surgery)
measure: Average time required for initial ureter identification (minutes)
timeFrame: 1 day (day of surgery)
measure: 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
timeFrame: 1 day (day of surgery)
measure: Among cases that normally require ureter skeletonization/ureter dissection, the proportion of cases where skeletonization/ureter dissection could be reduced or eliminated
timeFrame: 1 day (day of surgery)
measure: Average time period of ureter visualization provided by the first dose of Nizaracianine
timeFrame: 1 day (day of surgery)
measure: 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)
timeFrame: 1 day (day of surgery)
measure: Among subjects with ureter injury, the proportion of cases detected intraoperatively
timeFrame: 1 day (day of surgery)
measure: Among subjects with intraoperative detection of ureter injury, the proportion of cases in which Nizaracianine assisted repair
timeFrame: 1 day (day of surgery)
measure: For a particular surgical procedure type, average overall surgery time (Phase 3A only)
timeFrame: 1 day (day of surgery)
Other outcomes:
measure: In Phase 3A, comparison of the primary outcome measure between treatment and control arms
timeFrame: 1 day (day of surgery)
measure: In Phase 3B, comparison of the primary outcome measure between NIR imaging and white light imaging in the same subject
timeFrame: 1 day (day of surgery)
measure: In bladder-involved cases, the fraction of cases where Nizaracianine helped identify bladder anatomy
timeFrame: 1 day (day of surgery)
measure: The proportion of cases where Nizaracianine provided NIR fluorescence enhancement of blood vessels in the surgical field
timeFrame: 1 day (day of surgery)
Locations:
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Redwood City
country: United States
facility: Board of Trustees of Leland Stanford Junior University
state: California
city: Worcester
country: United States
facility: University of Massachusetts Chan Medical School
state: Massachusetts
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre (LUMC)
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Centre
Study officials:
affiliation: Curadel Surgical Innovations, Inc. (CSI)
name: John V Frangioni, M.D., Ph.D.
role: STUDY_CHAIR
affiliation: Curadel Surgical Innovations, Inc. (CSI)
name: Katherine T Scott, Ph.D.
role: STUDY_DIRECTOR
affiliation: Leiden University Medical Centre (LUMC)
name: Alexander L Vahrmeijer, M.D., Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: de Valk KS, Handgraaf HJ, Deken MM, Sibinga Mulder BG, Valentijn AR, Terwisscha van Scheltinga AG, Kuil J, van Esdonk MJ, Vuijk J, Bevers RF, Peeters KC, Holman FA, Frangioni JV, Burggraaf J, Vahrmeijer AL. A zwitterionic near-infrared fluorophore for real-time ureter identification during laparoscopic abdominopelvic surgery. Nat Commun. 2019 Jul 16;10(1):3118. doi: 10.1038/s41467-019-11014-1.