Study design and participants
hypersensitivity, cardiac disease
URETER, RETROPERITONEAL FIBROSIS, CARDIAC DISEASE, HEART, HYPERSENSITIVITY, URINARY TRACT INFECTION
This was a phase 2, randomized, open-label, dose-ranging clinical trial in adult participants undergoing laparoscopic, minimally invasive colorectal surgery in which the surgeon expected to encounter the ureter in the operative field. This study began on October 15, 2020 at two sites in the United States in accordance with the International Council for Harmonisation guidelines, applicable regulations and guidelines governing study conduct, and the ethical principles with their origin in the Declaration of Helsinki. An institutional review board/independent ethics committee approved the ethical, scientific, and medical appropriateness of the study and reviewed the protocol (and any amendments), written informed consent, and all other documentation prior to study initiation.Participants were randomly assigned by an interactive response technology system to receive a single dose of pudexacianinium (0.3 mg, 1.0 mg, or 3.0 mg) administered as an IV injection. The investigator defined the left or right ureter as the index ureter to be evaluated for anatomical visualization with a Stryker 1688 Advanced Imaging Modalities 4 K Platform (Stryker Corporation, Kalamazoo, MI) during surgery. Dose ranges were selected using pharmacokinetic (PK) modeling and simulation to provide differentiation around a central dose of 1.0 mg based on both nonclinical findings showing that a 0.01 mg/kg dose provided sufficient ureter visualization 3 h after IV administration [Investigator(s) and the sponsor’s medical and safety representatives met after three participants completed the surgical procedures at each dose level to determine whether to expand a dose under evaluation (up to 15 participants) or discontinue a dose under evaluation. The decision to expand or discontinue a dose was based on the totality of the collected data, including, but not limited to, anatomical visualization (defined as positive visualization of the ureter at both 30 min after dose administration and at the end of surgery) or fluorescence intensity based on a Likert scale (0 = none, 1 = mild, 2 = moderate, and 3 = strong).Eligible participants were aged ≥ 18 years and scheduled to undergo laparoscopic, minimally invasive colorectal surgery during which ureters needed to be visualized. Participants were required to have adequate liver, renal, and bone marrow function. Exclusion criteria included a history of known retroperitoneal fibrosis, active urinary tract infection, previous exposure to pudexacianinium, and hypersensitivity to pudexacianinium or ICG. Participants were not permitted to have received diuretics, renal transporter inhibitors, or other NIR-F imaging agents, or to have consumed alcohol within 48 h of the study. Additional exclusion criteria included moderate to severe cardiac disease (New York Heart Association Class III-IV), mean resting heart rate of ≤ 45 or ≥ 115 bpm, mean systolic or diastolic blood pressure of ≥ 160 mmHg or ≥ 100 mmHg, respectively, mean corrected QT interval using Fridericia’s formula (QTcF) > 430 ms (male) or > 450 ms (female), or if a requirement for ureteral stenting was anticipated during surgery. Participants enrolled after determination of the selected dose were permitted to have a body mass index (BMI) > 25 kg/m