Ureter Injury
Conditions
Brief summary
To determine whether the use of 3,3'-Dioxo-2,2'-Bisindolylidene-5,5'-Disulfonate Disodium 0.8% Solution for injection provides a visualization advantage compared to saline when used as an aid in the determination of ureteral patency
Detailed description
This is an open-label, randomized, multicenter study to evaluate the efficacy, safety, and pharmacokinetics of two doses (2.5 mL and 5.0 mL) of 3,3'-Dioxo-2,2'-bisindolylidene-5,5'-disulfonate disodium solution for injection when used as an aid in the determination of ureteral patency. Study will enroll up to 116 subjects from approximately 10 study centers in the United States.
Interventions
DRUG3,3'-Dioxo-2,2'-bisindolylidene-5,5'-disulfonate disodium 0.8%
Experimental contrast dye that is commonly used as a visualization aid in pelvic and abdominal surgeries and for various diagnostic procedures in medical practice.
DRUGSaline spray
Placebo
Sponsors
Prove pharm
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
DIAGNOSTIC
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Subjects between ≥ 18 and ≤ 85 years old. * Subjects who signed written, IRB approved, informed consent form. * Subjects scheduled for urological or gynecological surgical procedures in which the patency of the ureter must be assessed by the surgeon during the procedure
Exclusion criteria
* Subjects with stage 4 or 5 Chronic Kidney Failure as evidenced by a GFR \<30 mL/min/1.73m2 (using the MDRD) or need for dialysis in the near future, or having only 1 kidney. * Subjects with known severe hypersensitivity reactions to IC or other dyes including contrast agents. * Known history of drug or alcohol abuse within 6 months prior to the time of screening visit. * Subjects, as assessed by the Investigator, with conditions/concomitant diseases precluding their safe participation in this study (e.g. major systemic diseases). * Unable to meet specific protocol requirements (e.g., scheduled visits) or subject is uncooperative or has a condition that could lead to non-compliance with the study procedures. * Subject is the Investigator or any Sub-Investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol; * Subjects with life expectancy \< 6 months; * Requirement for concomitant treatment that could bias primary evaluation. * Subjects who are pregnant or breast-feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Urine Jet Conspicuity Score | 10 minutes | The urine jet conspicuity score provided by the blinded central review process as assessed by the following 5-point ordinal scale. 1. = No jet observed 2. = Weak jet, little color contrast 3. = Color contrast or significant jet flow 4. = Strong jet flow with good color contrast 5. = Strong jet flow with striking contrast in color |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Responders | 10 Minutes | A subject was a responder when there was ≥1-point improvement in the urine jet conspicuity scores following the indigo carmine versus saline treatment (indigo carmine - saline ≥1) and the conspicuity score following the indigo carmine treatment was 3, 4, or 5. The responder criteria were assessed separately for each ureter for each subject based on the blinded central reviewer's conspicuity score. |
| Physician Satisfaction Agreement Scale | 10 Minutes | After the completion of the procedure, the surgeon rated the experience of using indigo carmine for each subject using the 5-point PSAS, in which: Compared to the use of saline treatment, my ability to assess ureteral patency was improved after the addition of indigo carmine. 1. = Strongly Agree 2. = Agree 3. = Neither Agree nor Disagree 4. = Disagree 5. = Strongly Disagree The surgeon was considered satisfied with the indigo carmine treatment if his/her rating was either a 1 (strongly agree) or a 2 (agree); otherwise, the surgeon was considered unsatisfied with the indigo carmine treatment. |
| Time to Visualization | 10 Minutes | Time to visualization (minutes) of blue color in the ureteral jets flow following indigo carmine treatment |
Other
| Measure | Time frame | Description |
|---|---|---|
| Surgeon Urine Jet Conspicuity Score | 10 Minutes | The urine jet conspicuity score provided by the surgeon as assessed by the following 5-point ordinal scale. 1. = No jet observed 2. = Weak jet, little color contrast 3. = Color contrast or significant jet flow 4. = Strong jet flow with good color contrast 5. = Strong jet flow with striking contrast in color |
| Concordance of Conspicuity Scores | 10 Min | Concordance of conspicuity scores between the surgeons' assessments and the blinded central reviewer assessments. If the difference between raters in conspicuity score was within ±1 (ie, the difference ranged from 1 to +1, inclusive), the scores were considered to agree. The urine jet conspicuity score as assessed by the following 5-point ordinal scale. 1. = No jet observed 2. = Weak jet, little color contrast 3. = Color contrast or significant jet flow 4. = Strong jet flow with good color contrast 5. = Strong jet flow with striking contrast in color |
| Conspicuity Score Difference Between the Indigo Carmine High Dose and Indigo Carmine Low Dose by Central Review Process | 10 minutes | Exploratory analysis of the urine jet conspicuity score difference between the indigo carmine high dose and indigo carmine low dose by central review Process The urine jet conspicuity score provided by the blinded central review process as assessed by the following 5-point ordinal scale. 1. = No jet observed 2. = Weak jet, little color contrast 3. = Color contrast or significant jet flow 4. = Strong jet flow with good color contrast 5. = Strong jet flow with striking contrast in color |
| Conspicuity Score Difference Between the Indigo Carmine High Dose and Indigo Carmine Low Dose as Assessed by Surgeons Who Were Blinded to the Dose of Indigo Carmine | 10 Minutes | Exploratory analysis of conspicuity score difference between the indigo carmine high dose and indigo carmine low dose as assessed by surgeons who were blinded to the dose of indigo carmine The urine jet conspicuity score as assessed by the following 5-point ordinal scale. 1. = No jet observed 2. = Weak jet, little color contrast 3. = Color contrast or significant jet flow 4. = Strong jet flow with good color contrast 5. = Strong jet flow with striking contrast in color |
Countries
United States
Participant flow
Pre-assignment details
This was a crossover study where each subject served as their own control, so each subject received the control (saline solution) was evaluated for the endpoints and then received either the high or low dose based on their randomization assignment. So the total number of participants were 121 although each participant provided data for one of the active groups and the saline group.
Participants by arm
| Arm | Count |
|---|---|
| SALINE Then HIGH DOSE Approximately 48 subjects treated with 5 ml of saline than crossover to be treated with 5 mL of drug
3,3'-Dioxo-2,2'-bisindolylidene-5,5'-disulfonate disodium 0.8%: Experimental contrast dye that is commonly used as a visualization aid in pelvic and abdominal surgeries and for various diagnostic procedures in medical practice.
Saline solution: Placebo | 60 |
| SALINE Then LOW DOSE Approximately 48 subjects treated with 5 ml of saline than crossover to be treated with 2.5 mL of drug
3,3'-Dioxo-2,2'-bisindolylidene-5,5'-disulfonate disodium 0.8%: Experimental contrast dye that is commonly used as a visualization aid in pelvic and abdominal surgeries and for various diagnostic procedures in medical practice.
Saline solution: Placebo | 58 |
| Total | 118 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Planned procedure not performed after randomization, study drug not administered | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | SALINE Then HIGH DOSE | SALINE Then LOW DOSE | Total |
|---|---|---|---|
| Age, Customized < 65 years old | 42 Participants | 41 Participants | 83 Participants |
| Age, Customized >/= 65 years to <75 years old | 11 Participants | 12 Participants | 23 Participants |
| Age, Customized >/= 75 years old | 7 Participants | 5 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 8 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 50 Participants | 48 Participants | 98 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) White | 56 Participants | 49 Participants | 105 Participants |
| Region of Enrollment United States | 60 participants | 58 participants | 118 participants |
| Sex: Female, Male Female | 42 Participants | 45 Participants | 87 Participants |
| Sex: Female, Male Male | 18 Participants | 13 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 60 | 0 / 58 | 0 / 118 |
| other Total, other adverse events | 14 / 60 | 14 / 58 | 0 / 118 |
| serious Total, serious adverse events | 1 / 60 | 3 / 58 | 0 / 118 |
Outcome results
Primary
Urine Jet Conspicuity Score
The urine jet conspicuity score provided by the blinded central review process as assessed by the following 5-point ordinal scale. 1. = No jet observed 2. = Weak jet, little color contrast 3. = Color contrast or significant jet flow 4. = Strong jet flow with good color contrast 5. = Strong jet flow with striking contrast in color
Time frame: 10 minutes
Population: The efficacy analysis set, also referred to as the modified intent-to-treat (mITT) analysis set, included all subjects in the safety analysis set who had a surgical procedure to assess ureteral patency, who received both study drugs (saline and indigo carmine), and a video approximately 10 minutes in length was available after each treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIGH DOSE | Urine Jet Conspicuity Score | 4.1 score on a scale | Standard Deviation 1.34 |
| LOW DOSE | Urine Jet Conspicuity Score | 4.2 score on a scale | Standard Deviation 1.17 |
| Saline | Urine Jet Conspicuity Score | 2.5 score on a scale | Standard Deviation 1.1 |
p-value: <0.000195% CI: [7.394, 26.662]Score statistics for Type 3 GEE analysis
p-value: <0.000195% CI: [8.625, 32.617]Score statistics for Type 3 GEE analysis
Secondary
Percentage of Responders
A subject was a responder when there was ≥1-point improvement in the urine jet conspicuity scores following the indigo carmine versus saline treatment (indigo carmine - saline ≥1) and the conspicuity score following the indigo carmine treatment was 3, 4, or 5. The responder criteria were assessed separately for each ureter for each subject based on the blinded central reviewer's conspicuity score.
Time frame: 10 Minutes
Population: The efficacy analysis set, also referred to as the modified intent-to-treat (mITT) analysis set, included all subjects in the safety analysis set who had a surgical procedure to assess ureteral patency, who received both study drugs (saline and indigo carmine), and a video approximately 10 minutes in length was available after each treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| HIGH DOSE | Percentage of Responders | Responder | 43 Participants |
| HIGH DOSE | Percentage of Responders | Non-Responder | 6 Participants |
| LOW DOSE | Percentage of Responders | Responder | 41 Participants |
| LOW DOSE | Percentage of Responders | Non-Responder | 6 Participants |
95% CI: [78.6, 96.9]
95% CI: [77.7, 96.8]
Secondary
Physician Satisfaction Agreement Scale
After the completion of the procedure, the surgeon rated the experience of using indigo carmine for each subject using the 5-point PSAS, in which: Compared to the use of saline treatment, my ability to assess ureteral patency was improved after the addition of indigo carmine. 1. = Strongly Agree 2. = Agree 3. = Neither Agree nor Disagree 4. = Disagree 5. = Strongly Disagree The surgeon was considered satisfied with the indigo carmine treatment if his/her rating was either a 1 (strongly agree) or a 2 (agree); otherwise, the surgeon was considered unsatisfied with the indigo carmine treatment.
Time frame: 10 Minutes
Population: The efficacy analysis set, also referred to as the modified intent-to-treat (mITT) analysis set, included all subjects in the safety analysis set who had a surgical procedure to assess ureteral patency, who received both study drugs (saline and indigo carmine), and a video approximately 10 minutes in length was available after each treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| HIGH DOSE | Physician Satisfaction Agreement Scale | Satisfied (score of 1 or 2) | 44 Participants |
| HIGH DOSE | Physician Satisfaction Agreement Scale | Unsatisfied (Score of 3,4 or 5) | 5 Participants |
| LOW DOSE | Physician Satisfaction Agreement Scale | Satisfied (score of 1 or 2) | 38 Participants |
| LOW DOSE | Physician Satisfaction Agreement Scale | Unsatisfied (Score of 3,4 or 5) | 9 Participants |
95% CI: [78.2, 95.6]
95% CI: [67.5, 89.6]
Secondary
Time to Visualization
Time to visualization (minutes) of blue color in the ureteral jets flow following indigo carmine treatment
Time frame: 10 Minutes
Population: The efficacy analysis set, also referred to as the modified intent-to-treat (mITT) analysis set, included all subjects in the safety analysis set who had a surgical procedure to assess ureteral patency, who received both study drugs (saline and indigo carmine), and a video approximately 10 minutes in length was available after each treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HIGH DOSE | Time to Visualization | 6.00 Minutes |
| LOW DOSE | Time to Visualization | 5.93 Minutes |
95% CI: [5.25, 7]
95% CI: [5.12, 7]
Other Pre-specified
Concordance of Conspicuity Scores
Concordance of conspicuity scores between the surgeons' assessments and the blinded central reviewer assessments. If the difference between raters in conspicuity score was within ±1 (ie, the difference ranged from 1 to +1, inclusive), the scores were considered to agree. The urine jet conspicuity score as assessed by the following 5-point ordinal scale. 1. = No jet observed 2. = Weak jet, little color contrast 3. = Color contrast or significant jet flow 4. = Strong jet flow with good color contrast 5. = Strong jet flow with striking contrast in color
Time frame: 10 Min
Population: mITT Analysis Set; Subjects Without Missing Surgeon or Central Assessment Data
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| HIGH DOSE | Concordance of Conspicuity Scores | Right ureter | Disagreement | 2 Participants |
| HIGH DOSE | Concordance of Conspicuity Scores | Left Ureter | Agreement | 41 Participants |
| HIGH DOSE | Concordance of Conspicuity Scores | Right ureter | Agreement | 43 Participants |
| HIGH DOSE | Concordance of Conspicuity Scores | Left Ureter | Disagreement | 4 Participants |
| LOW DOSE | Concordance of Conspicuity Scores | Right ureter | Agreement | 37 Participants |
| LOW DOSE | Concordance of Conspicuity Scores | Right ureter | Disagreement | 6 Participants |
| LOW DOSE | Concordance of Conspicuity Scores | Left Ureter | Disagreement | 5 Participants |
| LOW DOSE | Concordance of Conspicuity Scores | Left Ureter | Agreement | 38 Participants |
| Saline | Concordance of Conspicuity Scores | Right ureter | Disagreement | 25 Participants |
| Saline | Concordance of Conspicuity Scores | Left Ureter | Disagreement | 21 Participants |
| Saline | Concordance of Conspicuity Scores | Right ureter | Agreement | 63 Participants |
| Saline | Concordance of Conspicuity Scores | Left Ureter | Agreement | 67 Participants |
Comparison: Left Ureter
Comparison: Left Ureter
Comparison: Left Ureter
Comparison: Right Ureter
Comparison: Right Ureter
Comparison: Right Ureter
Other Pre-specified
Conspicuity Score Difference Between the Indigo Carmine High Dose and Indigo Carmine Low Dose as Assessed by Surgeons Who Were Blinded to the Dose of Indigo Carmine
Exploratory analysis of conspicuity score difference between the indigo carmine high dose and indigo carmine low dose as assessed by surgeons who were blinded to the dose of indigo carmine The urine jet conspicuity score as assessed by the following 5-point ordinal scale. 1. = No jet observed 2. = Weak jet, little color contrast 3. = Color contrast or significant jet flow 4. = Strong jet flow with good color contrast 5. = Strong jet flow with striking contrast in color
Time frame: 10 Minutes
Population: mITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIGH DOSE | Conspicuity Score Difference Between the Indigo Carmine High Dose and Indigo Carmine Low Dose as Assessed by Surgeons Who Were Blinded to the Dose of Indigo Carmine | 4.2 score on a scale | Standard Deviation 1.31 |
| LOW DOSE | Conspicuity Score Difference Between the Indigo Carmine High Dose and Indigo Carmine Low Dose as Assessed by Surgeons Who Were Blinded to the Dose of Indigo Carmine | 4.2 score on a scale | Standard Deviation 1.26 |
p-value: 0.92295% CI: [0.509, 2.11]Score statistics for Type 3 GEE analysis
Other Pre-specified
Conspicuity Score Difference Between the Indigo Carmine High Dose and Indigo Carmine Low Dose by Central Review Process
Exploratory analysis of the urine jet conspicuity score difference between the indigo carmine high dose and indigo carmine low dose by central review Process The urine jet conspicuity score provided by the blinded central review process as assessed by the following 5-point ordinal scale. 1. = No jet observed 2. = Weak jet, little color contrast 3. = Color contrast or significant jet flow 4. = Strong jet flow with good color contrast 5. = Strong jet flow with striking contrast in color
Time frame: 10 minutes
Population: mITT Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIGH DOSE | Conspicuity Score Difference Between the Indigo Carmine High Dose and Indigo Carmine Low Dose by Central Review Process | 4.1 score on a scale | Standard Deviation 1.34 |
| LOW DOSE | Conspicuity Score Difference Between the Indigo Carmine High Dose and Indigo Carmine Low Dose by Central Review Process | 4.2 score on a scale | Standard Deviation 1.17 |
p-value: 0.459595% CI: [0.388, 1.534]Score statistics for Type 3 GEE analysis
Other Pre-specified
Surgeon Urine Jet Conspicuity Score
The urine jet conspicuity score provided by the surgeon as assessed by the following 5-point ordinal scale. 1. = No jet observed 2. = Weak jet, little color contrast 3. = Color contrast or significant jet flow 4. = Strong jet flow with good color contrast 5. = Strong jet flow with striking contrast in color
Time frame: 10 Minutes
Population: The efficacy analysis set, also referred to as the modified intent-to-treat (mITT) analysis set, included all subjects in the safety analysis set who had a surgical procedure to assess ureteral patency, who received both study drugs (saline and indigo carmine), and a video approximately 10 minutes in length was available after each treatment (subjects with missing data excluded).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIGH DOSE | Surgeon Urine Jet Conspicuity Score | 4.2 score on a scale | Standard Deviation 1.31 |
| LOW DOSE | Surgeon Urine Jet Conspicuity Score | 4.2 score on a scale | Standard Deviation 1.26 |
| Saline | Surgeon Urine Jet Conspicuity Score | 2.4 score on a scale | Standard Deviation 1.07 |
p-value: <0.000195% CI: [8.738, 43.663]Score statistics for Type 3 GEE analysis
p-value: <0.000195% CI: [7.199, 34.369]Score statistics for Type 3 GEE analysis