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)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 336
- 试验地点
- 18
- 主要终点
- The fraction of subjects for whom the surgeon is able to successfully identify the required length of the ureters (specified by the surgeon at each timepoint), as verified by three independent blinded reviewers.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Nizaracianine Triflutate Study Drug Arm
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 or 2.5 mg depending on trial phase.
干预措施: Nizaracianine Triflutate (Drug)
Sugar Comparator Arm
In Phase 3A only, ~50 subjects will be randomly allocated to receive sugar placebo.
干预措施: Placebo Comparator (Drug)
结局指标
主要结局
The fraction of subjects for whom the surgeon is able to successfully identify the required length of the ureters (specified by the surgeon at each timepoint), as verified by three independent blinded reviewers.
时间窗: 1 day (day of surgery)
The proportion of subjects for whom the surgeon is able to successfully identify the required length of the ureters (specified by the surgeon at each timepoint) with a peak signal-to-background ratio (SBR) ≥ 1.5 where SBR is signal-to-background ratio - verified by three independent blinded reviewers
次要结局
- Among cases that normally require ureter skeletonization/ureter dissection, the proportion of cases where skeletonization/ureter dissection could be reduced or eliminated(1 day (day of surgery))
- For a particular surgical procedure type, average overall surgery time (Phase 3A only)(1 day (day of surgery))
- The fraction of cases in which ureter identification did not require invasive procedures or dissection of surrounding tissue(1 day (day of surgery))
- Average time required for initial ureter identification (minutes)(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(1 day (day of surgery))
- Average time period of ureter visualization provided by the first dose of Nizaracianine(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)(1 day (day of surgery))
- Among subjects with ureter injury, the proportion of cases detected intraoperatively(1 day (day of surgery))
- Among subjects with intraoperative detection of ureter injury, the proportion of cases in which Nizaracianine assisted repair(1 day (day of surgery))