Application of ICG@HSA Complexes in Fluorescence Image-Guided Laparoscopic Anatomical Liver Resection

Randomized Controlled Trial Clinical Trial

Official title:

Application of Indocyanine Green(ICG)@Human Serum Albumin(HSA) Complexes in Fluorescence Image-Guided Laparoscopic Anatomical Liver Resection: A Prospective, Double-Blinded, Randomized Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06219096
• Other study ID #: IHLAP2121
• Status: Recruiting
• Phase: N/A
• Start date: December 10, 2023
• Est. completion date: December 31, 2028

Study information

• Verified date: January 2024
• Source: West China Hospital
• Contact: Hong Wu, Professor
• Phone: 18980601958
• Email: wuhong[@]scu.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is a single-center, prospective, randomized controlled trial that aims to compare the efficacy and safety of a new indocyanine green (ICG) administration protocol with the current guideline-recommended protocol for near-infrared (NIR) fluorescence imaging in laparoscopic anatomical hepatic resection. Primary liver cancer is a common malignancy worldwide. Laparoscopic liver resection has become increasingly popular due to its minimally invasive nature. During open and laparoscopic liver resection surgery, ICG, a fluorescent dye, is widely used to visualize liver segments and define tumor margins. However, there is a lack of high-level evidence regarding the timing and dosage of ICG administration in current protocols. In our preliminary study, we discovered a new method of pre-mixing ICG with albumin, which creates a more stable conjugate that could enhance fluorescence imaging during NIR laparoscopic hepatectomy. This study will include 100 patients with primary liver malignancies who are scheduled for laparoscopic anatomical hepatic resection. The patients will be randomly assigned in a 1:1 ratio to either the new ICG-albumin protocol (experimental group) or the standard ICG alone protocol (control group). The primary outcome will be the efficacy of fluorescence imaging, which will be evaluated using a 5-point scoring system by three independent experts. Secondary outcomes will include operation time, blood loss, tumor margin status, complications, length of stay, long-term recurrence, and survival.

The hypothesis of this study is that pre-binding ICG with albumin creates a more stabilized fluorescent complex, which could significantly improve the efficacy of fluorescence navigation and hepatectomy outcomes compared to standard ICG alone. This study aims to provide high-quality evidence on optimal protocols for ICG use in laparoscopic fluorescent image-guided liver surgery. The results of this study could help establish standardized guidelines to improve the application of this important navigation technique and enhance surgical precision and outcomes for liver cancer patients worldwide. The study protocol will be approved by the Ethics Review Board and publicly registered before enrollment starts. All participants will be required to provide informed consent. This study will be conducted in compliance with the Declaration of Helsinki and national regulations on human subject protection to ensure ethics, privacy, and safety.

Description:

1. Study Design:

This study is designed as a single center, prospective, randomized, double-blinded, controlled trial. The participants will be randomly assigned to either the experimental group (using the new ICG-albumin protocol) or the control group (using the standard ICG protocol) at a 1:1 ratio. The randomization will be done using a centralized web-based system.

2. Participants:

The study aims to enroll 100 patients aged 18-75 years old with primary liver malignancies who are planned for laparoscopic anatomical hepatic resection at our institution. The main inclusion criteria are a Child-Pugh grade A or B liver function and an ECOG performance score of 0-1. The main exclusion criteria include an ICG R15 value of >=20%, coagulation disorders, severe heart/lung disease, active bleeding, allergy to ICG, severe gastroesophageal varices, and pregnancy/lactation.

3. Interventions:

The interventions in the experimental group will involve mixing 0.5mg of ICG powder with 20mL saline containing 500mg of human albumin for at least 5 minutes. This mixture will then be intravenously infused at a rate of 1mL/min after occlusion of the target hepatic pedicles. On the other hand, the control group will receive a slow intravenous infusion of 2.5mg ICG (2.5mg/mL) following the current guidelines after pedicle occlusion.

4. Outcomes:

The primary outcome is the efficacy of fluorescence imaging, which will be evaluated by a 5-point scoring system by three independent experts. Secondary outcomes include operation time, blood loss, conversion to open surgery, parenchymal transection time, use of hemostatic clips, tumor margins, postoperative complications, liver function recovery, length of stay, long-term recurrence and survival. Safety outcomes include complications, mortality, and adverse reactions associated with ICG.

5. Participant Timeline:

Screening will take place within 2 weeks before surgery. Participants will be followed up during hospitalization. After discharge, follow-up will take place at month 1, 3, 6, 12, 18, 24, 30, 36 post-surgery.

6. Sample Size:

With a two-sided 0.05 significance level, 90% power, and expecting a 1-point improvement in fluorescence imaging efficacy score (SD 1.5), 49 participants per group are needed, 100 in total.

7. Data Collection and Management:

All data will be collected on paper case report forms and then entered into a centralized electronic data capture system. Data will go through quality check, cleaning, coding and logic validation. Any changes will be tracked. Cleaned and locked database will be used for final analysis. Original forms will be archived securely.

8. Statistical Analysis :

Efficacy of fluorescence imaging will be compared between groups using t-test or Mann-Whitney U test. Operation parameters will be analyzed by t-test or Wilcoxon rank test. Tumor margins will be evaluated by chi-square test. Complication rates will be compared using t-test or Fisher's exact test. Survival outcomes will be depicted by Kaplan-Meier curves and compared by Log-rank tests. Multivariate Cox regression will be used to identify factors affecting recurrence and survival. Sensitivity analysis will be performed to account for missing data.

9. Data Monitoring:

An independent data safety monitoring board will review study progress and safety data regularly. Any serious adverse events will be reported to investigators, IRB and regulatory agencies within 24 hours.

10. Ethics and Dissemination and Trial Status:

The study protocol will be approved by the IRB before initiation. All participants will provide written informed consent. Results will be disseminated through scientific conferences and peer-reviewed publications. The study is currently preparing for ethics submission and enrollment is expected to start in December 2023 and complete in November 2026.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: December 31, 2028
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Age: 18-75 years old, patients with hepatic malignancies who are undergoing laparoscopic anatomical liver resection;

2. Preoperative liver function Child-Pugh grade A or B;

3. No contraindications for laparoscopic liver resection;

4. Expected survival =3 months;

5. ECOG PS score 0-1;

6. Normal major organ functions, and meet the following laboratory test results within 7 days prior to enrollment: white blood cell (WBC) =2.5×10^9/L, absolute neutrophil count (ANC) =1.5×10^9/L, platelet (PLT) =75×10^9/L, hemoglobin (HGB) =90g/L; NR =1.5xULN; serum creatinine (CT) =1.5xULN; total bilirubin (TBI) =1.5×upper limit of normal (ULN);

7. Patients voluntarily participate and sign informed consent.

Exclusion Criteria:

1. No obvious ischemic demarcation line after intraoperative occlusion or disconnection of target hepatic pedicle, or the liver fluorescence reaches an intensity that interferes with surgery before intraoperative ICG injection.

2. Poor hepatic reserve function (ICG R15 = 20%);

3. Severe cardiopulmonary diseases, intolerant to general anesthesia and surgery;

4. Moderate or large amount of symptomatic ascites or pleural effusion;

5. Active bleeding or coagulation abnormalities;

6. Hepatic encephalopathy;

7. Allergy to ICG;

8. History of gastrointestinal bleeding within the past 6 months or definite tendency for gastrointestinal bleeding;

9. Severe esophageal gastric varices requiring interventional treatment;

10. Objective evidence showing severe impaired pulmonary function such as pulmonary fibrosis;

11. Any significant clinical and laboratory abnormalities that the investigator considers affecting safety assessment.

Related Conditions & MeSH terms

• Liver Neoplasms
• Randomized Controlled Trial

Intervention

Procedure:
• NIF image-guided laparoscopic anatomical liver resection with the novel ICG@HSA administration
After ligation of the target hepatic segmental portal vein, the novel ICG regimen (0.5 mg ICG powder and 500 mg human serum albumin added to 20 ml saline, shaken and allowed to stand for more than 5 minutes, ICG: 0.025 mg/ml, human serum albumin: 25 mg/ml) was intravenously infused continuously at a rate of 1 ml/min until significant fluorescence imaging appeared in the demarcated area, upon which the infusion was terminated.
• NIF image-guided laparoscopic anatomical liver resection with the guideline-recommended ICG administration
After ligation of the target hepatic segmental portal vein, 2.5 mg of ICG (2.5 mg/ml) was intravenously injected.

Locations

Country	Name	City	State
China	West China Hospital	Chendu	Sichuan

Sponsors (2)

Lead Sponsor	Collaborator
West China Hospital	Nanjing Chia-Tai Tianqing Pharmaceutical Company

Country where clinical trial is conducted

China, 

References & Publications (10)

Berardi G, Igarashi K, Li CJ, Ozaki T, Mishima K, Nakajima K, Honda M, Wakabayashi G. Parenchymal Sparing Anatomical Liver Resections With Full Laparoscopic Approach: Description of Technique and Short-term Results. Ann Surg. 2021 Apr 1;273(4):785-791. do — View Citation

Cai X, Hong H, Pan W, Chen J, Jiang L, Du Q, Li G, Lin S, Chen Y. Does Using Indocyanine Green Fluorescence Imaging for Tumors Help in Determining the Safe Surgical Margin in Real-Time Navigation of Laparoscopic Hepatectomy? A Retrospective Study. Ann Sur — View Citation

Chen H, Wang Y, Xie Z, Zhang L, Ge Y, Yu J, Zhang C, Jia W, Ma J, Liu W. Application Effect of ICG Fluorescence Real-Time Imaging Technology in Laparoscopic Hepatectomy. Front Oncol. 2022 Apr 6;12:819960. doi: 10.3389/fonc.2022.819960. eCollection 2022. — View Citation

Ishizawa T, Saiura A, Kokudo N. Clinical application of indocyanine green-fluorescence imaging during hepatectomy. Hepatobiliary Surg Nutr. 2016 Aug;5(4):322-8. doi: 10.21037/hbsn.2015.10.01. — View Citation

Itoh S, Tomiyama T, Morinaga A, Kurihara T, Nagao Y, Toshima T, Morita K, Harada N, Mori M, Yoshizumi T. Clinical effects of the use of the indocyanine green fluorescence imaging technique in laparoscopic partial liver resection. Ann Gastroenterol Surg. 2 — View Citation

Landsman ML, Kwant G, Mook GA, Zijlstra WG. Light-absorbing properties, stability, and spectral stabilization of indocyanine green. J Appl Physiol. 1976 Apr;40(4):575-83. doi: 10.1152/jappl.1976.40.4.575. — View Citation

Liu F, Wang H, Ma W, Li J, Liu Y, Tang S, Li K, Jiang P, Yang Z, He Y, Liu Z, Zhang Z, Yuan Y. Short- and Long-Term Outcomes of Indocyanine Green Fluorescence Navigation- Versus Conventional-Laparoscopic Hepatectomy for Hepatocellular Carcinoma: A Propens — View Citation

Wakabayashi T, Cacciaguerra AB, Abe Y, Bona ED, Nicolini D, Mocchegiani F, Kabeshima Y, Vivarelli M, Wakabayashi G, Kitagawa Y. Indocyanine Green Fluorescence Navigation in Liver Surgery: A Systematic Review on Dose and Timing of Administration. Ann Surg. — View Citation

Wang X, Teh CSC, Ishizawa T, Aoki T, Cavallucci D, Lee SY, Panganiban KM, Perini MV, Shah SR, Wang H, Xu Y, Suh KS, Kokudo N. Consensus Guidelines for the Use of Fluorescence Imaging in Hepatobiliary Surgery. Ann Surg. 2021 Jul 1;274(1):97-106. doi: 10.10 — View Citation

Xu Y, Chen M, Meng X, Lu P, Wang X, Zhang W, Luo Y, Duan W, Lu S, Wang H. Laparoscopic anatomical liver resection guided by real-time indocyanine green fluorescence imaging: experience and lessons learned from the initial series in a single center. Surg E — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Overall survival	Post-discharge follow-up (once every 3 months) using the follow-up center function of the professional EDC data management software to record follow-up via WeChat, questionnaires, and telephone calls	From date of randomization until death or loss to follow-up, up to 5 years
Other	Disease-free survival	Post-discharge follow-up (once every 3 months) using the follow-up center function of the professional EDC data management software to record follow-up via WeChat, questionnaires, and telephone calls	From the surgery was completed until disease progression or loss to follow-up, assessed up to 5 years
Primary	Fluorescence imaging effect of the live	The entire surgical video was recorded and then scored by experts	On the 7th day after surgery
Secondary	Duration of surgery	Based on the duration of the surgery as recorded	At the end of the surgery
Secondary	Intraoperative bleeding	Based on the amount of bleeding recorded during the surgery	At the end of the surgery
Secondary	Conversion to laparotomy	Based on intraoperative records to determine whether to convert to open laparotomy	At the end of the surgery
Secondary	Duration of hepatic parenchymal transection	Organize a dedicated person to review the surgical video and record the duration after the surgery is over	On the 7th day after surgery
Secondary	Number of hemostatic clips used on the liver transection surface	Organize a dedicated person to review the surgical video and record the duration after the surgery is over	On the 7th day after surgery
Secondary	Tumor margins	Specimen tumor margins will be measured by pathologists using calipers	At the end of the surgery
Secondary	Postoperative complications	Organize a dedicated person to record postoperative complications	Up to 24 weeks after surgery
Secondary	Postoperative hepatic function	Regularly measure liver function, coagulation, and other biochemical indicators after surgery after the patient returned to the ward	Up to 4 weeks after surgery
Secondary	Postoperative bowel function recovery time	Organize a dedicated person to record the time of rectal gas passage after surgery afer he patient returned to the ward	Up to 2 weeks after surgery
Secondary	Postoperative hospital stay	Organize a dedicated person to record the postoperative hospital stay	On the second day after discharge