Laparoscopic/Minimally Invasive Colorectal Surgery
Conditions
Keywords
ASP5354, ureter visualization, imaging agent, near infrared fluorescence
Brief summary
The primary purpose of this study was to determine the optimal dose of ASP5354 for ureter visualization in participants undergoing laparoscopic/minimally invasive colorectal surgery This study also investigated the safety, tolerability and the pharmacokinetics of ASP5354 in participants undergoing laparoscopic/minimally invasive colorectal surgery.
Detailed description
Participants were randomly assigned at each dose level (dose A, B, C). During a standard minimally invasive surgery, visualization of the surgical field was assessed following the placement of the near infrared fluorescence (NIR F) imaging system proximal to the ureter of interest and then ASP5354 was administered. Based on Visualization Review Committee (VRC) review of the initial 3 dose levels, if none of the doses selected had visualization, then additional two dose levels (dose D and E) was planned to be added; if 1 dose selected has visualization, then the dose level D was planned to be added. The dose level F was planned to be added if only the dose E level has visualization.
Interventions
Intravenous
Sponsors
Astellas Pharma Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject is scheduled to undergo laparoscopic/minimally invasive colorectal surgery. * Subject will need visualization of the ureter(s). * Female subject is not pregnant and at least 1 of the following conditions apply: * Not a woman of childbearing potential (WOCBP) * WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 30 days after final study treatment administration. * Female subject must agree not to breastfeed starting at screening and throughout the study period. * Female subject must not donate ova starting at first dose of investigational product (IP) and throughout the study period and for 30 days after final study treatment administration. * Male subject with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for 30 days after final study treatment administration. * Male subject must not donate sperm during the treatment period and for 30 days after final study treatment administration. * Male subject with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 30 days after final study treatment administration. * Subject agrees not to participate in another interventional study while participating in the present study. * Subjects enrolled after optimal dose determination: Subject has any of the following values at screening: * Body mass index \> 25 * Estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m\^2 and \< 60. Subjects with an eGFR ≥ 60 mL/min/1.73 m\^2 may be considered after discussion with the medical monitor.
Exclusion criteria
* Subject is anticipated to require ureteral stenting during surgery. * Subject has a history of known retroperitoneal fibrosis. * Subject has an active urinary tract infection. * Subject has received any investigational therapy within 28 days or 5 half-lives, whichever is longer, prior to screening. * Subject has any condition that makes the subject unsuitable for study participation. * Subject has a known or suspected hypersensitivity to ASP5354, indocyanine green (ICG) or any components of the formulation used. * Subject has had previous exposure to ASP5354. * Subject has moderate to severe cardiac disease that limits daily functioning (New York Heart Association Class III-IV) or other medical conditions that the investigator feels would impact safety or study compliance. * Subject has a mean resting heart rate ≤ 45 bpm or ≥ 115 bpm, mean systolic blood pressure (SBP) ≥ 160 mmHg or mean diastolic blood pressure (DBP) ≥ 100 mmHg on day -1. If the mean blood pressure exceeds the limits above, repeat readings can be taken. Subject who has adequately controlled blood pressure is eligible. * Subject has a mean corrected QT interval (Triplicate electrocardiogram \[ECG\]) using Fridericia's formula (QTcF) \> 430 msec (for male subjects) and \> 450 msec (for female subjects) on day -1. If the mean QTcF exceeds the limits above, the mean of 1 additional triplicate ECG may be taken. * Subject has any of the following screening laboratory values: * Hemoglobin ≤ 9 g/dL * Absolute neutrophil count ≤ 1500/µL * Platelet count ≤ 100000/µL * eGFR \< 60 mL/min/1.73 m\^2 (Not applicable to subjects enrolled after optimal dose determination.) * Serum bilirubin ≥ 2 × upper limit of normal (ULN) * Aspartate aminotransferase (AST) or serum glutamic oxaloacetic transaminase ≥ 2.5 × ULN * Alanine aminotransferase (ALT) or serum glutamic pyruvic transaminase ≥ 2.5 × ULN * Subject has taken ICG or other near-infrared fluorescence (NIR)-F imaging agents within 48 hours prior to study treatment administration. * Subject has taken diuretics or inhibitors of renal transporters defined by Food and Drug Administration (FDA) within 48 hours prior to study treatment administration. * Subject has used any illicit drugs, unless legally prescribed and is not being abused (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine and opiates) within 1 month prior to day -1. * Subject has a history of alcohol abuse. Subject should not have consumed any alcohol within 48 hours of surgery.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Successful Anatomical Visualization of the Index Ureter(s) | 30 minutes postdose through end of surgery (on day 1) | The anatomical visualization of the index ureter(s) was assessed by the investigator intraoperatively using a binary Yes or No question on the ability to visualize the ureter and was assessed as successful, if both 30 minutes after pudexacianinium chloride dosing and at end of surgery the visualization was assessed as positive (Yes)/successful. For imputation of missing values at 30 minutes after pudexacianinium chloride administration, the nearest time points before and after the 30 minutes was considered. If both time points (before and after 30 minutes) were successful, 30 minutes anatomical visualization was imputed as successful. If both time points were not successful, then 30 minutes anatomical visualization was imputed as not successful, and all other cases were not imputed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Urine Concentration of Pudexacianinium Chloride | Predose, 10, 30, 60, 90 minutes, end of surgery, 180 mins post dose | Urine concentration of pudexacianinium chloride was reported from the urine samples collected. Concentrations below the lower limit of quantification (20 ng/mL) are set to zero. |
| Amount of Pudexacianinium Chloride Excreted in Urine (Ae) During Surgery | During surgery (on day 1) | Amount of pudexacianinium chloride excreted in urine during surgery was reported. |
| Percentage of Pudexacianinium Chloride Dose Excreted Into Urine (Ae%) During Surgery | During surgery (on day 1) | Percentage of pudexacianinium chloride dose excreted into urine during surgery was reported. |
| Number of Participants With Treatment Emergent Adverse Events | From first dose of study drug until follow-up period (day 10) | An adverse event (AE) was any untoward medical occurrence in a participant administered an investigational product (IP), and which did not necessarily have a causal relationship with the treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of IP whether or not considered related to the IP. A TEAE was defined as an AE observed after administration of the IP and up to the follow-up period. An AE was considered serious if the event: results in death;is life-threatening; results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions;results in congenital anomaly, or birth defect;requires inpatient hospitalization (except for planned procedures as allowed per study) or leads to prolongation of hospitalization; Other medically important events. |
| Plasma Concentration of Pudexacianinium Chloride | Predose, 10, 30, 60, 90, 120 minutes, end of surgery, 180 mins post dose | Plasma concentration of pudexacianinium chloride was reported from the blood samples collected. Concentrations below the lower limit of quantification (1 nanogram per milliliter \[ng/mL\]) are set to zero. |
Countries
United States
Participant flow
Recruitment details
Participants undergoing laparoscopic/minimally invasive colorectal surgery in which the need for anatomical visualization of the ureter was anticipated were enrolled into this study.
Pre-assignment details
Eligible participants who met inclusion criteria and none of the exclusion criteria were enrolled. A total of 13 participants were randomized, of which 12 participants received study drug.
Participants by arm
| Arm | Count |
|---|---|
| Pudexacianinium Chloride - Dose Level A Participants received single dose of pudexacianinium chloride at dose level A by IV bolus infusion on day 1 once the surgical area of interest is in view. | 3 |
| Pudexacianinium Chloride - Dose Level B Participants received single dose of pudexacianinium chloride at dose level B by IV bolus infusion on day 1 once the surgical area of interest is in view. | 3 |
| Pudexacianinium Chloride - Dose Level C Participants received single dose of pudexacianinium chloride at dose level C by IV bolus infusion on day 1 once the surgical area of interest is in view. | 3 |
| Pudexacianinium Chloride - Dose Level B - Dose Expansion Participants who were enrolled in the dose expansion group received single dose of pudexacianinium chloride at dose level B by IV bolus infusion on day 1 once the surgical area of interest is in view. | 3 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Miscellaneous | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Pudexacianinium Chloride - Dose Level A | Pudexacianinium Chloride - Dose Level B | Pudexacianinium Chloride - Dose Level C | Pudexacianinium Chloride - Dose Level B - Dose Expansion | Total |
|---|---|---|---|---|---|
| Age, Continuous | 55.3 years STANDARD_DEVIATION 2.5 | 56.7 years STANDARD_DEVIATION 11.6 | 38.3 years STANDARD_DEVIATION 12.4 | 57.3 years STANDARD_DEVIATION 5.7 | 51.9 years STANDARD_DEVIATION 11.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 1 Participants | 2 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 3 Participants | 3 Participants | 2 Participants | 10 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 2 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 1 / 3 | 2 / 3 | 1 / 3 | 1 / 3 |
| serious Total, serious adverse events | 2 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Percentage of Participants With Successful Anatomical Visualization of the Index Ureter(s)
The anatomical visualization of the index ureter(s) was assessed by the investigator intraoperatively using a binary Yes or No question on the ability to visualize the ureter and was assessed as successful, if both 30 minutes after pudexacianinium chloride dosing and at end of surgery the visualization was assessed as positive (Yes)/successful. For imputation of missing values at 30 minutes after pudexacianinium chloride administration, the nearest time points before and after the 30 minutes was considered. If both time points (before and after 30 minutes) were successful, 30 minutes anatomical visualization was imputed as successful. If both time points were not successful, then 30 minutes anatomical visualization was imputed as not successful, and all other cases were not imputed.
Time frame: 30 minutes postdose through end of surgery (on day 1)
Population: FAS Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pudexacianinium Chloride - Dose Level A | Percentage of Participants With Successful Anatomical Visualization of the Index Ureter(s) | 66.7 percentage of participants |
| Pudexacianinium Chloride - Dose Level B | Percentage of Participants With Successful Anatomical Visualization of the Index Ureter(s) | 100.0 percentage of participants |
| Pudexacianinium Chloride - Dose Level C | Percentage of Participants With Successful Anatomical Visualization of the Index Ureter(s) | 100.0 percentage of participants |
| Pudexacianinium Chloride - Dose Level B - Dose Expansion | Percentage of Participants With Successful Anatomical Visualization of the Index Ureter(s) | 66.7 percentage of participants |
Secondary
Amount of Pudexacianinium Chloride Excreted in Urine (Ae) During Surgery
Amount of pudexacianinium chloride excreted in urine during surgery was reported.
Time frame: During surgery (on day 1)
Population: PKAS population with available data at specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pudexacianinium Chloride - Dose Level A | Amount of Pudexacianinium Chloride Excreted in Urine (Ae) During Surgery | 0.0670 milligrams (mg) | Standard Deviation 0.0239 |
| Pudexacianinium Chloride - Dose Level B | Amount of Pudexacianinium Chloride Excreted in Urine (Ae) During Surgery | 0.212 milligrams (mg) | Standard Deviation 0.0339 |
| Pudexacianinium Chloride - Dose Level C | Amount of Pudexacianinium Chloride Excreted in Urine (Ae) During Surgery | 1.19 milligrams (mg) | Standard Deviation 0.371 |
| Pudexacianinium Chloride - Dose Level B - Dose Expansion | Amount of Pudexacianinium Chloride Excreted in Urine (Ae) During Surgery | 0.0438 milligrams (mg) | — |
Secondary
Number of Participants With Treatment Emergent Adverse Events
An adverse event (AE) was any untoward medical occurrence in a participant administered an investigational product (IP), and which did not necessarily have a causal relationship with the treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of IP whether or not considered related to the IP. A TEAE was defined as an AE observed after administration of the IP and up to the follow-up period. An AE was considered serious if the event: results in death;is life-threatening; results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions;results in congenital anomaly, or birth defect;requires inpatient hospitalization (except for planned procedures as allowed per study) or leads to prolongation of hospitalization; Other medically important events.
Time frame: From first dose of study drug until follow-up period (day 10)
Population: The safety analysis set (SAF) consisted of all randomized participants who received pudexacianinium chloride.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pudexacianinium Chloride - Dose Level A | Number of Participants With Treatment Emergent Adverse Events | 2 participants |
| Pudexacianinium Chloride - Dose Level B | Number of Participants With Treatment Emergent Adverse Events | 2 participants |
| Pudexacianinium Chloride - Dose Level C | Number of Participants With Treatment Emergent Adverse Events | 1 participants |
| Pudexacianinium Chloride - Dose Level B - Dose Expansion | Number of Participants With Treatment Emergent Adverse Events | 1 participants |
Secondary
Percentage of Pudexacianinium Chloride Dose Excreted Into Urine (Ae%) During Surgery
Percentage of pudexacianinium chloride dose excreted into urine during surgery was reported.
Time frame: During surgery (on day 1)
Population: PKAS population with available data at specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pudexacianinium Chloride - Dose Level A | Percentage of Pudexacianinium Chloride Dose Excreted Into Urine (Ae%) During Surgery | 22.3 percentage of drug excreted | Standard Deviation 7.98 |
| Pudexacianinium Chloride - Dose Level B | Percentage of Pudexacianinium Chloride Dose Excreted Into Urine (Ae%) During Surgery | 21.2 percentage of drug excreted | Standard Deviation 3.39 |
| Pudexacianinium Chloride - Dose Level C | Percentage of Pudexacianinium Chloride Dose Excreted Into Urine (Ae%) During Surgery | 39.5 percentage of drug excreted | Standard Deviation 12.4 |
| Pudexacianinium Chloride - Dose Level B - Dose Expansion | Percentage of Pudexacianinium Chloride Dose Excreted Into Urine (Ae%) During Surgery | 4.38 percentage of drug excreted | — |
Secondary
Plasma Concentration of Pudexacianinium Chloride
Plasma concentration of pudexacianinium chloride was reported from the blood samples collected. Concentrations below the lower limit of quantification (1 nanogram per milliliter \[ng/mL\]) are set to zero.
Time frame: Predose, 10, 30, 60, 90, 120 minutes, end of surgery, 180 mins post dose
Population: The pharmacokinetic analysis set (PKAS) consisted of all randomized participants who received pudexacianinium chloride and had at least 1 plasma or urine concentration data available with the time of dosing and sampling. Participants with available data at specified time point were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pudexacianinium Chloride - Dose Level A | Plasma Concentration of Pudexacianinium Chloride | Predose | 0 ng/mL | Standard Deviation 0 |
| Pudexacianinium Chloride - Dose Level A | Plasma Concentration of Pudexacianinium Chloride | 10 Minutes | 48.9 ng/mL | Standard Deviation 20.6 |
| Pudexacianinium Chloride - Dose Level A | Plasma Concentration of Pudexacianinium Chloride | 30 Minutes | 22.5 ng/mL | Standard Deviation 3.3 |
| Pudexacianinium Chloride - Dose Level A | Plasma Concentration of Pudexacianinium Chloride | 60 Minutes | 15.3 ng/mL | — |
| Pudexacianinium Chloride - Dose Level A | Plasma Concentration of Pudexacianinium Chloride | 90 Minutes | 12.7 ng/mL | — |
| Pudexacianinium Chloride - Dose Level A | Plasma Concentration of Pudexacianinium Chloride | 120 Minutes | 8.37 ng/mL | — |
| Pudexacianinium Chloride - Dose Level A | Plasma Concentration of Pudexacianinium Chloride | End of Surgery | 14.0 ng/mL | Standard Deviation 5.98 |
| Pudexacianinium Chloride - Dose Level B | Plasma Concentration of Pudexacianinium Chloride | Predose | 0 ng/mL | Standard Deviation 0 |
| Pudexacianinium Chloride - Dose Level B | Plasma Concentration of Pudexacianinium Chloride | 10 Minutes | 196 ng/mL | Standard Deviation 161 |
| Pudexacianinium Chloride - Dose Level B | Plasma Concentration of Pudexacianinium Chloride | 60 Minutes | 38.2 ng/mL | Standard Deviation 7.35 |
| Pudexacianinium Chloride - Dose Level B | Plasma Concentration of Pudexacianinium Chloride | 30 Minutes | 58.0 ng/mL | Standard Deviation 5.74 |
| Pudexacianinium Chloride - Dose Level B | Plasma Concentration of Pudexacianinium Chloride | 90 Minutes | 34.4 ng/mL | — |
| Pudexacianinium Chloride - Dose Level B | Plasma Concentration of Pudexacianinium Chloride | 180 Minutes | 18.0 ng/mL | — |
| Pudexacianinium Chloride - Dose Level B | Plasma Concentration of Pudexacianinium Chloride | End of Surgery | 28.0 ng/mL | Standard Deviation 1.64 |
| Pudexacianinium Chloride - Dose Level C | Plasma Concentration of Pudexacianinium Chloride | 30 Minutes | 146 ng/mL | Standard Deviation 46.1 |
| Pudexacianinium Chloride - Dose Level C | Plasma Concentration of Pudexacianinium Chloride | Predose | 0 ng/mL | Standard Deviation 0 |
| Pudexacianinium Chloride - Dose Level C | Plasma Concentration of Pudexacianinium Chloride | 60 Minutes | 106 ng/mL | — |
| Pudexacianinium Chloride - Dose Level C | Plasma Concentration of Pudexacianinium Chloride | 10 Minutes | 322 ng/mL | Standard Deviation 177 |
| Pudexacianinium Chloride - Dose Level C | Plasma Concentration of Pudexacianinium Chloride | End of Surgery | 47.3 ng/mL | Standard Deviation 29.8 |
| Pudexacianinium Chloride - Dose Level B - Dose Expansion | Plasma Concentration of Pudexacianinium Chloride | End of Surgery | 51.0 ng/mL | Standard Deviation 14.7 |
| Pudexacianinium Chloride - Dose Level B - Dose Expansion | Plasma Concentration of Pudexacianinium Chloride | 30 Minutes | 81.1 ng/mL | Standard Deviation 16.2 |
| Pudexacianinium Chloride - Dose Level B - Dose Expansion | Plasma Concentration of Pudexacianinium Chloride | 10 Minutes | 272 ng/mL | Standard Deviation 278 |
| Pudexacianinium Chloride - Dose Level B - Dose Expansion | Plasma Concentration of Pudexacianinium Chloride | Predose | 0 ng/mL | Standard Deviation 0 |
| Pudexacianinium Chloride - Dose Level B - Dose Expansion | Plasma Concentration of Pudexacianinium Chloride | 180 Minutes | 41.5 ng/mL | — |
Secondary
Urine Concentration of Pudexacianinium Chloride
Urine concentration of pudexacianinium chloride was reported from the urine samples collected. Concentrations below the lower limit of quantification (20 ng/mL) are set to zero.
Time frame: Predose, 10, 30, 60, 90 minutes, end of surgery, 180 mins post dose
Population: PKAS population with available data at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pudexacianinium Chloride - Dose Level A | Urine Concentration of Pudexacianinium Chloride | End of Surgery | 1960 ng/mL | Standard Deviation 955 |
| Pudexacianinium Chloride - Dose Level A | Urine Concentration of Pudexacianinium Chloride | 10 Minutes | 0 ng/mL | — |
| Pudexacianinium Chloride - Dose Level A | Urine Concentration of Pudexacianinium Chloride | Predose | 0 ng/mL | Standard Deviation 0 |
| Pudexacianinium Chloride - Dose Level B | Urine Concentration of Pudexacianinium Chloride | 30 Minutes | 10800 ng/mL | Standard Deviation 8620 |
| Pudexacianinium Chloride - Dose Level B | Urine Concentration of Pudexacianinium Chloride | 60 Minutes | 12000 ng/mL | Standard Deviation 7420 |
| Pudexacianinium Chloride - Dose Level B | Urine Concentration of Pudexacianinium Chloride | 90 Minutes | 6800 ng/mL | — |
| Pudexacianinium Chloride - Dose Level B | Urine Concentration of Pudexacianinium Chloride | 180 Minutes | 953 ng/mL | — |
| Pudexacianinium Chloride - Dose Level B | Urine Concentration of Pudexacianinium Chloride | Predose | 0 ng/mL | Standard Deviation 0 |
| Pudexacianinium Chloride - Dose Level B | Urine Concentration of Pudexacianinium Chloride | 10 Minutes | 695 ng/mL | Standard Deviation 983 |
| Pudexacianinium Chloride - Dose Level B | Urine Concentration of Pudexacianinium Chloride | End of Surgery | 4840 ng/mL | Standard Deviation 3650 |
| Pudexacianinium Chloride - Dose Level C | Urine Concentration of Pudexacianinium Chloride | Predose | 0 ng/mL | Standard Deviation 0 |
| Pudexacianinium Chloride - Dose Level C | Urine Concentration of Pudexacianinium Chloride | End of Surgery | 33800 ng/mL | Standard Deviation 636 |
| Pudexacianinium Chloride - Dose Level B - Dose Expansion | Urine Concentration of Pudexacianinium Chloride | Predose | 0 ng/mL | Standard Deviation 0 |