Objectives and hypothesis
The primary aim of the Robotic Assisted Radical Prostatectomy with EXacyl (RARPEX) trial is to investigate the effect of tranexamic acid on perioperative and postoperative blood loss (decrease in hemoglobin levels) in robotic-assisted radical prostatectomy.
H0: The drop of hemoglobin level after the procedure is similar in both groups.
HA: The drop of hemoglobin level after the procedure in control group is higher than in study group.
The secondary aim of the RARPEX trial is to analyze the effect of tranexamic acid on postoperative complications.
H0: The rate of postoperative complications within 90 days after the procedure is similar in both groups.
HA: The rate of postoperative complications within 90 days after the procedure is different between the groups.
Additional end-point of the RARPEX trial is to confirm the safety of tranexamic acid in robotic assisted radical prostatectomy.
Study population and eligibility criteria
All patients who are scheduled for operation due to low or intermediate risk prostate cancer in our institution will be screened and assessed for eligibility.
Only patients who will undergo robotic assisted radical prostatectomy with suturing of dorsal complex vein (DVC) bundle at the beginning of the procedure without pelvic lymph node dissection will be included in the study. Patients with nonstandard procedures or a procedure associated with higher morbidity will be excluded from the study to achieve a homogeneous study group.
Detailed inclusion and exclusion criteria are described below.
Inclusion criteria
- Patient scheduled for robotic assisted radical prostatectomy without pelvic lymph node dissection
- Signed informed consent provided
- Body mass index ≤ 35
- Age of patient ≤ 75 years
- Operating surgeon with experience of more than 100 cases
Exclusion criteria
- Body mass index > 35
- Age of the patient > 75 years
- Coagulation disorder (congenital or iatrogenic due to the chronic use of anticoagulants)
- Thromboembolic, cerebral, or an acute coronary event within the 6 months prior to prostatectomy
- Chronic renal insufficiency (arbitrary cut-off level of creatinine 200 µmol/l)
- Allergic reaction to tranexamic acid
- Operating surgeon with experience < 100 cases
- Patient participating in another study
If subjects do not meet the inclusion criteria or withdraw their consent, they will be excluded from the study. The researcher will record the reason for their withdrawal.
Sample size calculation
The sample size calculation is based on the data from our pilot study (27). We used a Two-Sample T-Tests Allowing Unequal Variance with respect to the primary endpoint, which is the drop of hemoglobin level. With α = 1% and β = 10%, a sample size of 64 patients per group is necessary to detect a clinically significant difference between the groups. With an expected dropout rate over 33%, we plan to enroll 200 patients into the study.
Ethics, study registration and consent
This trial was approved by independent ethics committee at the University Hospital Hradec Kralove (registration number 201903 I90P). The RARPEX trial will be conducted in the context of Good Clinical Practice and in accordance with the Declaration of Helsinki. The trial is registered at ClinicalTrials.gov under the registration number NCT04319614. All patients who are scheduled for robotic assisted radical prostatectomy in our institutions will be screened for eligibility and informed in detail about the RARPEX trial. Informed consent will be obtained from each participant. The study procedures, risks, benefits, and data management will be clarified with the patients before they are asked to give their informed consent to participate. Any participant in this study may withdraw consent or voluntarily cease to participate at any time for any reason.
Study treatment
Based on the literature and our pilot study (27), we decided to administer a single dose of tranexamic acid, corresponding to 20 mg/kg in 100 ml saline to all patients in the treatment group 1 at the beginning of procedure. In the control group 2 we administer only 100 ml saline as placebo.
For prophylaxis of venous thromboembolism, the combination of mechanical device (graduated compression stockings) and pharmacologic agents (low-molecular-weight-heparin - LMWH) in both treatment groups will be used. The dose LMWH is administered in the evening before the procedure, next dose at least 8 hours after the procedure and then every evening till postoperative day (POD) 7.
Antibiotic prophylaxis is provided by a single dose of potent aminopenicillin as recommended by the antibiotic center; fluoroquinolone in patients with an allergy to aminopenicillin. During the procedure, the console time, and weight of prostate is monitored.
The surgical technique is standardized and has been described previously (28). Standard robotic-assisted radical prostatectomy without pelvic lymphadenectomy using DaVinci Xi surgical system is performed. The dorsal vein complex (DVC) is sutured in the beginning of the procedure with two rounds of resorbable monofilament suture. To accelerate the return of continence, a modified Rocco stitch is performed in all patients. The anastomosis is performed by two tied V-loc stitches. No additional manipulation, such as fibrin glue or reinforcement with meshes, is allowed. Patients with rectal or bowel injury during the procedure will be excluded from evaluation.
For three hours after the procedure patients of both groups will stay in intermediate care unit, after moving to standard ward, blood samples will be obtained. On POD 1 all the patients will start with mobilization and solid food intake. The volume of the fluids in drain will be measured on postoperative day 1 and if the volume will not exceed 200 ml for 24 hours the drain will be extracted. If the volume is higher than 200 ml / 24 hours and the creatinine level in drain fluid exceeds 500 µmol/l, urinary leakage will be confirmed (29).
On POD 2 the patients will be released for home care with indwelling permanent urinary catheter.
On POD 7 the urinary catheter and skin sutures will be extracted and the blood sampling and ultrasound of the lower abdomen will be performed. Three months after the procedure a follow up visit is scheduled. The evidence of complication and level of prostatic specific antigen (PSA) is monitored.
Upon completion in 200 patients the statistical processing will be performed, and patients will be unblinded.
Safety aspects
Robotic assisted radical prostatectomy is a highly technically demanding procedure. High-volume surgeons with great experience have better results than low-volume surgeons with less experience (30).
In order to avoid bias based on the learning curve of the surgeons, every surgical procedure will be performed by a senior surgeon who has experience with at least 100 robotic assisted radical prostatectomies. Administration of tranexamic acid at the beginning of the procedure by anesthesiologist is a simple common procedure, performed on a routine basis, and no special training is necessary, and no complications are expected.
Data collection
A daily visit of the study patients will be made by clinical investigators or a delegated physician. All protocol-required information collected during the trial will be entered into the patient’s record form. Preoperative data gathered include patient age, body mass index, American Society of Anesthesiologists physical status classification system score and comorbidities. Intraoperative data to be collected include surgery duration (skin to skin), console time (console surgeon activity time), and weight of the prostate.
According to data from our pilot study (27), we are not able to measure perioperative blood loss, because of many biases. The volume of suction fluid is affected by urine coming out of open urinary tract, lymphatic secretion from damaged tissue.
Laboratory tests will include blood count and plasmatic creatinine level at the beginning of procedure, 3–6 hours after the procedure, on POD 1, POD 2 and POD 7 in the morning.
The differences between the hemoglobin levels (eventually weighted for the grams of the prostatic tissue) and hemoglobin / creatinine ratios are obtained.
The volume of the fluids in drain is measured on postoperative day 1 and if the volume does not exceed 200 ml for 24 hours the drain is extracted. If the volume is higher than 200 ml / 24 hours and creatinine level in the drain fluid exceeds 500 µmol/l urinary leakage is confirmed (29). Patient with confirmed urinary leakage or urinoma will be excluded from the evaluation.
Postoperative course assessments will include duration of intermediate / intensive care, hospital stay including readmissions for postoperative complications, reinterventions (reoperations, endoscopy and interventional radiology procedures), the reasons for readmissions and transfusion rates. The patients will be seen by a clinical investigator 3 months after the surgery in the outpatient fashion. The evidence of complication and level of prostatic specific antigen (PSA) is monitored. Upon completion of 200 patients the statistical processing will be performed, and results will be unblinded.
Primary and secondary endpoints
The primary endpoint is to analyze the effect of tranexamic acid on perioperative and postoperative blood loss – the decrease in hemoglobin levels after robotic-assisted radical prostatectomy. Clinically significant difference between treatment groups is set at 10 g/l. We assume that the results will be significantly affected by the weight of the prostate. A larger prostate could mean longer operating time and greater blood loss. Therefore, the results are weighted for the grams of the prostatic tissue. Another potential bias could be different hydration of subjects before, during and after the procedure. Therefore, the hemoglobin / creatinine ratio was used.
The secondary aim of the RARPEX trial is to analyze the effect of tranexamic acid on other postoperative complications: wound infection, intraabdominal collections, urinary leakage, delayed gastro-intestinal emptying, postoperative hemorrhage, pneumonia, abdominal rupture (Table 1).
Additional end-point of the RARPEX trial is to confirm the safety of tranexamic acid in robotic assisted radical prostatectomy, especially analyzing the incidence of cardiac events and venous thromboembolism (VTE) after the procedure.
Table 1 Clinical parameters and postoperative complications for analysisa
Parameters Definitions
Hospital stay Days from initial operation to hospital discharge plus any readmission
within 30 days
Console time Time of console surgeon activity (minutes)
Postoperative Evidence of blood loss from drains, based on ultrasonography or CT
haemorrhage
Transfusion rate The number of blood transfusions
Urinary leakage Evidence of creatinine level > 500 μmol/l and volume of the drain output
exceeds 200ml / 24 hours, confirmed on cystography
Lymphorrhea Evidence of creatinine level < 500 μmol/l, hematocrit< 0,2 and volume
of the drain output exceeds 200ml / 24 hours, no urinary leakage on cystography
Intraabdominal fluid Collection of fluid measuring ≥3 cm associated with clinical or laboratory
collection abnormalities
Symptomatic Fluid in the pleural cavity associated with respiratory distress or a need to
fluidothorax evacuate the fluid
Thromboembolism Unilateral limb swelling, acute respiratory insufficiency, based
on ultrasonography or CT
Myocardial infarction Increase of serum concentration of CK-MB and troponin and/or the following
ECG changes: new Q waves ≥0.04 in duration, new persistent ST elevation
and/or depression
Brain stroke Presence of neurological symptoms, findings on CT scan or MRI
Pneumonia Presence of a new infiltrate on chest X-ray, as well as the following: body
temperature >38°C, abnormal elevation of WBC, or positive sputum, and
requiring antibiotic treatment
Acute renal failure Serum creatinine > 300 μmol/l and/or need for dialysis
Wound infection Surgical site infection associated with laparotomy that develops during the
initial hospital stay
Urinary tract infection Culture-positive urine, pyuria or bacteriuria on urinalysis requiring antibiotic
treatment
aCK-MB, Creatine kinase MB isoenzyme; ECG, Electrocardiogram; WBC, White blood cells; CT, Computer tomography; MRI, Magnetic resonance imaging.
Postoperative complications are graded based on severity according to the Clavien-Dindo definition (Table 2) (31).
Table 2 - Complication grades according to the Dindo-Clavien classification scheme
Grade Definition
Grade I Any deviation from the normal postoperative course without the need for
pharmacological treatment or surgical, endoscopic and radiologic intervention
Grade II Requiring pharmacological treatment with drugs other than those allowed for grade I
complications
Grade III Requiring surgical, endoscopic or radiological intervention
Grade IIIa Intervention not under general anesthesia
Grade IIIb Intervention under general anesthesia
Grade IV Life-threatening complications requiring intensive care unit management
Grade IVa Single-organ dysfunction
Grade IVb Multiorgan dysfunction
Grade V Death of the patient
Methods for avoiding bias
Minimizing systemic bias
Patients will be randomized to one of groups before the surgical procedure after meeting eligibility criteria. Randomization will be accomplished using balanced permutation blocks by generation of random numbers in order to obtain homogeneity between groups. Opaque, sealed envelopes will be produced, labeled with the randomization number and containing a sheet that states the group allocation for the patient. Randomization envelopes will be used in consecutive order. Basic characteristics of the patient and the day of randomization will be documented on a data sheet so that compliance to the randomization scheme may be checked retrospectively. To maintain the double-blinding, the placebo and active ingredient are identical and cannot be distinguished by appearance by the participants or staff. The code assigned to subjects will be kept sealed and will not be released until the end of the clinical trial. Cases in which the blinding must be unsealed, such as a serious adverse drug reaction, will be managed using a separate envelope created for each subject so that only their randomization is revealed. Randomization and blinding will not be revealed to the researchers until the end of the study. If patients are excluded from the study after randomization, their numbers will not be reused.
Unblinded nurse will prepare an infusion set according to the information in the sealed envelope with the patient's study number on the day of procedure. For patients in the intervention group 1, the dose of tranexamic acid according to target 20mg/kg will be added to 100 ml of physiological saline. For patients in the intervention group 2 she will add no other substance to 100 ml of physiological saline. Infusion will be given into the sealed envelope, sent to the operating theatre and given within 5 minutes after the robotic system is docked.
Operating surgeons, attending physicians, nursing staff and outcome assessors will be blinded. The randomization process will follow the CONSORT guidelines (32) (Fig. 1).
Minimizing treatment bias
Administration of tranexamic acid at the beginning of the procedure by anesthesiologist is a simple common procedure, performed on a routine basis, which eliminates a learning curve.
All patients will undergo robotic-assisted radical prostatectomy without pelvic lymphadenectomy using the same technique. All surgeons participating in the study are familiar with this procedure. The dorsal vein complex (DVC) will be sutured at the beginning of procedure.
Minimizing measurement bias
Measurement of hemoglobin level drop and detection and grading postoperative complications will be based on data in the patient’s record form. Patient and clinical investigators or a delegated physician will be blinded.
Statistical methods
Each patient’s allocation to the analyzed population will be defined prior to the analysis and will be documented. In the full-analysis set, patients will be analyzed as randomized according to the intention-to-treat principle. The intention-to-treat principle implies that the analysis includes all randomized patients. The per-protocol analysis set will include all the patients without major protocol deviation. Deviations from the protocol will be assessed as major or minor. Patients with major deviations from the protocol will be excluded from the protocol analysis. The safety analysis set will analyze patients according to the treatment. The null hypothesis assumes that there is no difference in the hemoglobin level drop after the procedure in both groups. We will use a Two-Sample T-Tests Allowing Unequal Variance with respect to the endpoint, which is the drop of hemoglobin levels. Differences between age and PSA will be assessed by the nonparametric Mann-Whitney U test. BMI and specimen weight will be compared by the Kolmogorov-Smirnov test. A P-value < 0,05 will be considered statistically significant. Statistical analyses will be performed using NCSS statistical software (NCSS, Kaysville, UT, USA).