Study setting {9}
The BLUEPATH study is not yet recruiting. It is planned to initiate the study in the Czech Republic in March 2022.
St. Anne´s University Hospital Brno, the coordinating center for the study, is responsible for the education and training of research staff, tracking participants’ enrolment, mathematical analysis, monitoring, pharmacovigilance, data management, and reporting of the study.
Eligibility criteria {10}
A patient may be included in the clinical trial if they meet all of the following criteria:
- Age ≥ 18 years
- Subpleural deposited pulmonary lesion/s with the need for further histological diagnosis, which is:
- localized at a depth of 0 to 30 mm below the pleura
- less than 40 mm length subsolid with a solid component greater than 6 mm with growth progression according to the Lung-RADS criteria (version 1.1) ((Chelala et al. 2021))
- clearly not infiltrating the parietal pleura according to CT examination
- Cognitive fitness and health status of the patient enabling a full understanding of the information about the clinical trial and the signing of informed consent
- Participants in the clinical trial of childbearing potential must agree to the use of prescribed contraceptive methods for the duration of this clinical trial:
- Women - Proper use of a highly reliable method of contraception, i.e. combined hormonal contraception (oral, vaginal, or transdermal dosage form), gestagen hormonal contraceptives associated with ovulation inhibition (oral or injectable dosage form), non-hormonal intrauterine device, or intrauterine device releasing hormones, eventually the presence of bilateral tubal occlusion, a partner's vasectomy, or adherence to sexual abstinence.
- Men - Adherence to sexual abstinence or the use of an adequate contraceptive method (i.e. condom) in case of sexual intercourse.
4.2. Exclusion criteria
A patient must not be included in the clinical trial if he meets any (at least one) of the following criteria:
- Pregnancy or breast-feeding
- History of hypersensitivity/allergy to patent blue or triphenylmethane dyes contained in medicinal products, food, or cosmetics
- Hypersensitivity/allergy or history of severe adverse reactions to iodine or iodine contrast agents (e.g. severe renal impairment after previous administration of iodine contrast agent)
- Hypersensitivity/allergy to excipients in IMP
- Hypersensitivity/allergy to trimecaine, or other local anesthetics
- Manifest hyperthyroidism or thyrotoxicosis
- Scheduled thyroid scan, thyroid function test, or radioiodine treatment
Who will take informed consent? {26a}
The study protocol including the informed consent will be reviewed and approved by the Institutional Review Board of the sites and by the National Regulatory Authority – The State Institute of Drug Control. A trained study investigator will describe the study to patients or to authorized surrogates if applicable. Patients will also receive information sheets. The investigator will discuss the study with patients in the sense of the information provided in the information sheets. The investigator will obtain written informed consent from patients willing to participate in the trial. In the case of patients who are unable to consent because of a medical condition, their ability to participate in the study will be assessed by a medical council consisting of at least one independent physician informed about the study details and one study investigator.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
A part of the informed consent will be dedicated to reusing the data obtained in the proposed study to improve the current clinical practice and to disseminate evidence-based medicine. The study conforms to the Consolidated Standards of Reporting Trials (CONSORT) guidelines.
Interventions
Explanation for the choice of comparators {6b}
Not applicable. A comparator is not used in this study. The patients will be randomized into 2 groups in a 1:1 ratio. The first group will undergo VATS wedge resection of lung deposits marked with patent blue and contrast agent iohexol under CT-guided control. The second group will undergo VATS resection without prior color coding of the lung deposits.
Intervention description {11a}
1. Patient selection phase
Cases of patients with incidents are normally discussed at St. Anne´s University Hospital Brno multidisciplinary lung commissions, in the presence of a surgeon, radiologist, oncologist, and pulmonary physician. The activities of the physicians of the indication commissions will take place in the regime of routine clinical practice and will not be part of this clinical trial. Patients meeting the indication criteria will then be ordered for admission to the 1st Department of Surgery, Faculty of Medicine, Masaryk University, University Hospital St. Anne´s Brno. From these patients, the investigator will select individuals with potential for inclusion in the study according to the inclusion and exclusion criteria.
2. Hospital admission - day 0
From the day of admission to the 1st day of admission, the patient will be offered participation in the clinical trial and will be interviewed by examining physicians (interventional radiologist and surgeon) who will clearly explain the method of marking the lung deposits and surgery. Further aspects of participation in the clinical trial and its potential risks and benefits will be explained. If the patient agrees to participate in the clinical trial, he/she will give informed consent.
A pregnant woman's blood or urine test will be performed on women of childbearing potential. On the day of admission, the patient will be randomized into one of 2 groups (1st control group, 2nd group undergoing lesion staining, and subsequent resection) using the randomizer.org web software. All patients complete the SF-36 questionnaire on the day of admission.
3. Scheduled Surgery Day - Day 1
On the day of the planned surgery, patients from the control group will be transported directly to the operating room, where they will undergo surgery under general anesthesia with selective ventilation in the lateral position (see also point b) Bearing resection).
In all patients included in the group with color-coded lung deposits, a chest CT will be performed on the day of the planned operation, during which the monitored lesions will be re-examined. In the case of multiple foci, the most suspicious and optimally localized foci will be selected by both the radiologist and the surgeon for both marking and subsequent resection.
The patient will be positioned on a mobile CT table. The position (side-lying, on the abdomen, on the side) will be chosen directly according to the previous CT so as to minimize the radiation dose for the bearing and to make the access puncture trajectory as suitable and safe as possible. After alignment using coordinate points on the CT image, the injection site point will be precisely selected and a route to the selected subpleural deposited area or district for subsequent resection will be planned. The procedure takes place under aseptic cautery, after skin disinfection, sterile masking of the operating field and after local anesthesia with trimecaine (Mesocain 1% inj. sol). The patient will have a peripheral vein secured by an intravenous cannula throughout the procedure.
a) Preparation of marking mixture and its application
After instillation of the local anesthetic, the radiologist prepares an examination marking mixture on CT under aseptic conditions. This is followed by withdrawal of 1 ml of Omnipaque 350 mg L/ml solution for injection into a sterile syringe. He then changes the needle, takes 2 ml of Patent Blue V Sodium Injection 2.5% from the ampoule, and mixes the mixture in a syringe.
Subsequently, a thin needle will be inserted into the preselected part of the lungs under CT control. The needle is introduced on inspiration, gradually, by the step-by-step method, with an emphasis on the most accurate placement of the needle tip to the observed lesion. We will pass the needle through the pleura only when the direction of the needle is in the intended trajectory so that the pleural leaf is broken by only one penetration. When the needle is in a suitable location, about 0.5 ml of the prepared mixture will be instilled into the pulmonary area.
A common and natural reaction to the application of the mixture is a cough. Therefore, after instillation of the marking mixture, the needle will be immediately withdrawn on inspiration to prevent lung injury from the coughing. At the end of the marking procedure, a control CT scan will be performed on a short scale to clarify the distribution of the mixture and possible complications (bleeding, pneumothorax). The patient will then be transported directly to the operating room accompanied by the surgeon for their own operation. The patient will be under the supervision of a radiologist and surgeon throughout the procedure at the Radiology Department. All acquired CT scans will be stored in the PACS system.
b) Deposit resection
The blue dye serves as an exact indication of the location of the deposit, the region marked in this way is visually identified by the operator. The contrast agent in the substance performs the task of verifying the distribution and exact instillation of the color mixture on the CT image, i.e. as close as possible to the site of the observed pathology. For the control group, the identification of the lesion will be performed palpably through surgical instruments or palpably by a surgeon through the surgical port, if technically possible.
In the operating theatre, the patient will undergo surgery under general anesthesia with selective ventilation in the lateral position, the operated lung will not be ventilated during the operation. First, a thoracic camera will be introduced into the thoracic cavity through a port (entrance) of about 1 cm, followed by an aspect of the thoracic cavity with visual verification of the marked area. The marked/selected area will then be wedge-shaped (extra anatomically) resected using endo staplers through one or two established working ports. The operation will be completed by checking the operating field and introducing a thoracic drain used to detect leakage (tightness of the lung parenchyma), restore vacuum in the thoracic cavity, and control the amount and nature of secretion from the thoracic cavity. Postoperatively, the patient will be transferred to the ICU, where he will have a first lung X-ray two hours after the operation to verify the position of the chest drain and check the lung parenchyma.
4. Postoperative phase - day 2-30
The patient will be hospitalized in the ICU, where a series of control lung X-rays will be performed. The 2nd X-ray will be performed at the time of the reduction of the chest suction to the 8 cm water column, the 3rd X-ray will be performed after the extraction of the thoracic drain, the 4th image will be taken during the inspection in the outpatient clinic during suture extraction (7th - 14th postoperative day).
The result of histological examination of the marked area is usually available within 10 days of the operation, it will be available and stored in the patient's medical records. After discharge from the hospital by day 30, the patient will be monitored at the clinical trial center by the examining physicians. Day 30 is the date of termination of the patient's participation in the clinical trial.
After the end of the participation, the patient will be monitored in any thoracic pneumatological or oncological outpatient clinic.
Criteria for discontinuing or modifying allocated interventions {11b}
The trial participant has the right to terminate participation in this clinical trial at any time and for any reason, or without stating it.
The investigator must:
- instruct the evaluation body on the right to early termination of participation
- inform him/her that the termination of participation would not affect the physician's approach, the method of further treatment or its quality,
- ask him/her to discuss this decision with the investigator in advance,
- enter in the documentation the date of early termination of the entity's participation and the reason, if known.
- Other reasons for early termination of the entity's participation include:
- allergic reaction to investigational medicinal products,
- non-marking of the bearing due to technical complications,
- the examiner's decision that further patient involvement is not in the patient's best interests;
- persistent or repeated non-cooperation of the patient, or loss of contact with the patient,
- pregnancy of a patient participating in the clinical trial,
- termination of the study by a decision of the sponsor or the regulatory authority.
Strategies to improve adherence to interventions {11c}
Training before initialization will ensure compliance during the whole study. If there are doubts, a chief investigator is designated to address them.
Relevant concomitant care permitted or prohibited during the trial {11d}
Due to the intrapulmonary administration of the study treatment, there are no restrictions on the concomitant treatment of chronic diseases, acute conditions, or other pharmacotherapy administered during the study.
Provisions for post-trial care {30}
Using the procedure of colour marking and subsequent resection of bearings using the VATS method, we assume shortening the hospital stay, reducing the amount of analgesic therapy, increasing patient comfort, and in some cases, speeding up diagnosis. Compared to classic thoracotomy, the respiratory function of the lungs is fully preserved during and after the procedure, the procedure is significantly less painful and there is no atrophy of the latissimus dorsi muscle (K. Yoshida et al. 2011). The method is generally well tolerated by patients and is not burdened with significant risks. A control group of patients will undergo resection of the lesions using a mini-invasive VATS method without the use of prior staining of the lesions.
Risks for BLUEPAT study participants may include allergic reactions to both the staining agent and the iodine contrast agent or local anesthetic. Despite its mini-invasive nature, increased pain may occur during the procedure, which can be corrected by administering analgesics. Bleeding into the lungs, pleural space, or chest wall can sometimes occur after a subcutaneous puncture. However, these are usually not life-threatening events. These conditions can be effectively diagnosed by a control scan, which serves to verify the distribution of the labeling mixture immediately after puncture and labeling. One of the most common complications after a puncture is pneumothorax. It is solved according to the extent, either by simple manual air aspiration or by chest drainage ((Yamagami et al. 2002)). Serious complications, which undoubtedly include potentially fatal pulmonary embolism, are described in the literature as very rare ((Freund et al. 2018)). In the event of leakage of the marking mixture into the pleural space and insufficient staining of the lesion area, or, conversely, ingestion of the dye and staining of a large area of lung tissue, it may be necessary to convert the procedure to classic thoracotomy. During intrabronchial application of the blue dye, it is subsequently coughed up. The use of CT-guided control is also related to the higher radiation exposure to which the patient is exposed during the procedure. In very rare cases, infection and pneumonia may develop. The possible side effects of the investigational drugs (patent blue and contrast agent iohexol) are listed in the Summary Product of Characteristics.
Outcomes {12}
The primary outcome of the clinical trial is to demonstrate the benefit of labeling subpleural deposited pulmonary foci. The following parameters will be monitored to evaluate the primary objective:
1) Success of the designated marking under CT control and simultaneous visualization of the marked area by the surgeon
Monitored parameters:
- comparison of the visibility of the marking contrast on the CT by the radiologist and the visibility of the marked blue area preoperatively by the surgeon, possibilities: radiologist YES/surgeon YES, radiologist YES/surgeon NO
- percentage evaluation of "in sano" resections
2) Intensity, severity, and frequency (incidence) of adverse events and reactions according to established Adverse Events of Special Interest (AESIs)
All AEs and with special attention the following AESIs will be used as monitored parameters:
- mild and moderate AESIs - mantle pneumothorax smaller than 2 cm not requiring acute chest drainage, bleeding not requiring surgery, allergic reactions - rash
- severe and life-threatening AESIs - mantle pneumothorax larger than 2 cm requiring acute chest drainage, bleeding requiring surgery, pulmonary embolism, anaphylactic reaction
3) Evaluation of postoperative pain using VAS ((Hawker et al. 2011))
Monitored parameters: visual analog scale for pain assessment, grades 0 (no pain) to 10 (maximum pain)
4) Occurrence of intraoperative complications (yes/no, if yes: description of complication, duration, treatment)
Monitored parameters: inability to identify VATS lesions by approach, bleeding, lung parenchymal injury, intrathoracic injury, conversion to thoracotomy (YES/NO)
5) Occurrence of postoperative pulmonary and cardiovascular complications (yes/no, if yes: description of the complication, duration, treatment)
Monitored parameters: the necessity of reoperation, the necessity of red drainage, amount of secretion from the thoracic drain/24 hours after surgery (ml/24h), postoperative leak after 24 hours after surgery (YES/NO)
6) Consumption of analgesics
Monitored parameters: preparation, dose, dosing interval, duration of administration
The secondary objectives and parameters are the following:
1) Detailed characteristics of the deposit
- Deposit typing according to the Lung-RADS (version 1.1 from 2019) ((Chelala et al. 2021)) and subsequent correlation with pathological findings after resection
- Percentage evaluation of benign and malignant etiology of deposits
- Location of the lesion in the lung parenchyma (designation of the lung segment), its size (volume in cm3), and subpleural depth of the lesion (in mm from the parietal pleura)
2) Feasibility of the marking method
- Total radiologist time from the arrival at CT (minutes)
- Total time from the end of radiologist marking to the visualization of the lesion by the surgeon (minutes)
- Presence of coloring substance outside the marked area (parietal pleura, mediastinum, free thoracic cavity) - evaluated by the surgeon perioperatively (YES/NO)
- Comparison of the volume of the marked area after resection with the size of the solid deposit on CT (the pathologist supplies 3 dimensions of the resection to calculate its volume (a x b x c) in cm3, the radiologist calculates the volume of the solid deposit according to the dimensions from the CT)
3) Additional safety information
- Evaluation of postoperative X-ray findings 2 hours after surgery, at the time of reduction of chest suction to 8 cm water column, 2 hours after chest drain extraction, and at the time of suture extraction during outpatient examination (7th - 14th postoperative day)
- Total thoracic drainage time (days)
- Length of hospitalization (days)
- Length of stay in the ICU (days)
- Postoperative quality of life according to the SF-36 questionnaire
- 30-day mortality (YES/NO)
Participant timeline {13}
The schedule of enrolment, intervention and visits is summarized in Table 1: Participant timeline. The duration of the study participation in a given patient is 30 days.
Sample size {14}
We plan to include 30 patients in each group. Due to an expected 10-20 % dropout rate, it will require 72 subjects to be recruited to accrue an adequate sample size to demonstrate a significant difference between the two study groups. The sample size was estimated based on our pilot retrospective study. Expected mean values hospital LOS (6 days for the control group and 4 days for the PBV group), with standard deviation (SD) of 2, power 0.90, and p=0.01 were used for sample size estimation.
Recruitment {15}
Recruitment of the patients is planned to commence in March 2022. During the first two years, all planned patients shall be recruited. The patients will be recruited within cooperating centers in the Czech Republic.
The patient will be informed about the study before the surgery or by a telephone call, during which initial eligibility for the study will be determined, and the study protocol and design will be explained by the research staff.
Assignment of interventions: allocation
Sequence generation {16a}
The recruited patients will be randomized to intervention – PBV group and controls in the ratio 1:1. Patients randomized in the PBV group will undergo preoperative lung node staining.
Patients randomized to the control group will undergo surgery without delay. Intraoperative and post-operative complications will be monitored the same way as in the intervention – PBV group.
Concealment mechanism {16b}
Statistica software 12.0 (StatSoft Inc., Prague, Czech Republic) will be used for statistical analysis. Web-based software like e.g. randomizer.org will be used for randomization.
Implementation {16c}
The study investigator will enroll the participants.
The other collaboration centres are responsible for patients´ selection according to the eligibility criteria, adherence to all criteria of the study as described below, and enrolling the participants.
Assignment of interventions: Blinding
Who will be blinded {17a}
Not applicable. This study is not blinded.
Procedure for unblinding if needed {17b}
Not applicable. This study is not blinded.
Data collection and management
Plans for assessment and collection of outcomes {18a}
The study will collect demographic and baseline characteristics from medical records and electronic medical records, including age, sex, type of admission, and baseline characteristics such as body weight, body height, patient history, and pharmacological history. Results of CT scans and physical examination will be documented in the electronic medical records and entered by the trial investigator in the electronic Case Report Form (eCRF).
Plans to promote participant retention and complete follow-up {18b}
The study site will make every reasonable effort to follow the participant for the entire study period. Study site staff members will be responsible for developing and implementing local standard operating procedures to achieve maximal follow-up.
Data management {19}
The study data will be entered online in an Internet-based database (RedCap®) and collected from medical records. The study staff members will have access to the medical records of the patients. The investigators will be responsible for screening patients, obtaining informed consent, collecting study data, and entering it into the eCRF. The statistician will analyze the study data in cooperation with the principal investigator. The data will be stored for 15 years after completion of the study and then destroyed. To promote data quality, the eCRFs of each participant will be reviewed by another member of the study team as a monitor.
Confidentiality {27}
All study-related information will be stored securely at the study site. All participant information will be stored in locked file cabinets in areas with limited access. All local databases will be secured with password-protected access systems. Forms, lists, logbooks, appointment books, and any other listings that link participant ID numbers to add identifying information will be stored in a separate locked file in an area with limited access.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Not applicable. In this study, no biological specimens for genetic or molecular analysis will be collected.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Primary outcomes were set up as the
- Intra-operative complications
- Post-operative pulmonary and cardiovascular complications
- Post-operative pain and analgesics consumption
Secondary endpoints are designed:
- ICU and hospital length of stay
- Postoperative quality of life
- 30 days mortality
The Shapiro-Wilk test will be used to evaluate normality. Comparisons between subjects will be done using the Student t-test and Mann-Whitney U test. Differences in proportions will be tested by the two-tailed Fisher exact test. Data will be summarized as mean ± standard deviation (SD); p values <0.05 will be considered statistically significant. Statistica software 12.0 (StatSoft Inc., Prague, Czech Republic) will be used for statistical analysis. Web-based software like e.g. randomizer.org will be used for randomization.
Interim analyses {21b}
Not applicable. An interim analysis is not planned.
Methods for additional analyses (e.g. subgroup analyses) {20b}
Not applicable. Additional analysis is not planned.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
No analysis populations are defined for this study. Protocol non-adherence will be assessed by the principal investigator case by case. Patients with major protocol deviations will be excluded from the analysis.
Missing data are not planned to be imputed. However, in the event of substantial missing data for any parameter, a sensitivity analysis using any method of imputation could also be used.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
Data sharing statement: No later than three years after the collection of data from the last patient’s final visit in the second year, we will deliver a completely anonymized data set to an appropriate data archive for sharing purposes. Statistical codes will be archived following GCP and SOPs.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
Not applicable. No coordinating center or a trial steering committee will be established.
Composition of the data monitoring committee, its role and reporting structure {21a}
Not applicable. No data monitoring committee will be established. The study interventions such as designated marking are parts of the standard care.
Adverse event reporting and harms {22}
Serious adverse events will be reported according to standard rules and standard operating procedures of the coordinating unit. All study participants will be monitored for potential adverse events.
Frequency and plans for auditing trial conduct {23}
Trial conduct will be audited by the Institutional Ethics Committee every year during the study. The process of auditing will be independent of the investigator and sponsor.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Any modifications of the protocol that may affect the conduct of the study, the potential benefits to the patient, or patient safety, including changes in study objectives, study design, patient population, sample sizes, study procedures, or significant administrative aspects, will require a formal amendment of the protocol. Any amendments will be agreed on and approved by the ethics committee before implementation, and the health authorities will be notified, in accordance with local regulations. The protocol amendment will be sent to all members of the study team by e-mail. All attending investigators and study nurses of the study units will be acquainted with the amendment at a meeting. The invitation to the meeting will be sent by e-mail. The protocol of the study and its amendments will be available at each study unit.
Dissemination plans {31a}
We intend to submit the results of the study to be published in a peer-reviewed international medical journal.