Prospective Evaluation of Near-infrared Fluorescence Imaging Use as a Supportive Tool in Deep Infiltrating Endometriosis Surgery (GRE-Endo-2)

Indocyanine Green and Near-Infrared Vision in Deep Infiltrating Endometriosis Surgery. A Prospective Study (GRE-Endo-2 Trial)

The aim of the study is to establish a new and more accurate method to visualize the peritoneal changes caused by endometriosis using Indocyanine Green mediated fluorescence imaging. The hypothesis is that Indocyanine Green, a fluorescent dye that has wide applications throughout medicine in identifying vascularity of tissues and neo-vascularization, could facilitate the localization and excision of endometriotic lesions exploiting the hypervascularization due to the chronic inflammation. The already published Pilot Study GRE-ENDO (Cosentino F, Near-Infrared Imaging with Indocyanine Green for Detection of Endometriosis Lesions (Gre-Endo Trial): A Pilot Study.), encouraged the effort of a larger prospective trial. Based on the mini-max two-stage design by Simon [Simon R. Optimal two stage design for phase II clinical trials], the investigators tested the null hypothesis that the true rate of pathologically assessed endometriosis would improve from 87% to the clinically relevant alternative of 100.0%, as assessed by NIR-ICG laparoscopy.

Study Overview

• Status: Completed
• Conditions: Pelvic Endometriosis; Endometriosis Outside Pelvis
• Intervention / Treatment: Drug: Indocyanine Green

Detailed Description

Patients were recruited within the clinical routine after indication for laparoscopy under consideration of the inclusion and exclusion criteria.

The sample size was calculated according to the study design by Simon (Simon R. Optimal two stage design for phase II clinical trials), using an α-error of 0.01 (two-sided) and a β-error of 0.90. Considering a patient dropout of approximately 10%, the study was planned to enrol at least 47 women.

The first abdominal and pelvi's inspection was made using direct laparoscope visualization under white light conditions. All areas suspected of peritoneal endometriosis was classified as white, black and red lesions and recorded together with their anatomic location in the surgical record for the purposes of subsequent extirpation. After the first visual inspection the patient was administered with 0.05 - 0.25 mg /(kg BW) Indocyanine Green intravenously. The Indocyanine Green imaging mode of the Olympus Indocyanine Green Imaging System was activated and suspected areas in Indocyanine Green imaging mode were recorded with them corresponding appearance in white light mode. If suspected areas were visible either in white light or Indocyanine Green imaging mode, specific sample has been taken from these areas. In addition, control biopsy specimens from inconspicuous peritoneum has been taken.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • RM
    • Rome, RM, Italy, 00100
      • Catholic University Of Sacred Heart

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 48 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Suspected endometriosis with necessity for laparoscopic confirmation and resection
• Regular menstrual cycles

Exclusion Criteria:

• Patients younger than 18 years and older than 50 years at time of operation
• Subject with previous history of adverse reaction or allergy to Indocyanine Green, iodine, shellfish or iodine dyes
• Documented allergy to sulfur containing compounds
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to Indocyanine Green
• Subject has significant liver disease, cirrhosis or liver insufficiency with abnormal liver function tests (Total bilirubin increased by factor 1.5 than normal and/or serum glutamic oxaloacetic transaminase increased by factor 2 than normal)
• Subject has uremia, serum creatinine (> 2.0 mg/dl)
• Subject has severe coronary heart disease (instable angina pectoris)
• Pregnant or breast-feeding women
• Subject actively participating in another drug, biologic and/or device protocol
• The presence of medical conditions contraindicating general anesthesia or standard surgical approaches
• Subject has any medical condition, which in the judgment of the Investigator and/or designee makes the subject a poor candidate for the investigational procedure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Indocyanine Green arm; All the patients to be enrolled have to meet the inclusion criteria. All enrolled patient is subjected, during laparoscopy, to an accurate inspection of the abdomen and all the visible endometriotic lesions are described. Subsequently, 0.25 mg /(kg BW) Indocyanine Green is administered intravenously during surgery and a second look of the abdomen and pelvis with the Near Infrared Vision is made, in order to identify the fluorescent lesions. All the lesions are described and localized pre and post the Indocyanine Green injection and then removed and properly cataloged.

Drug: Indocyanine Green; 0.25 mg /(kg BW) Indocyanine Green PULSION®/ VERDYE Diagnostic Green® - Indocyanine Green is administered Intravenously

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Localization of occult endometriotic lesion	To detect occult endometriotic lesions, thanks to the fluorescence of the Indocyanine Green, that would remain otherwise not visible to the surgeon eye	Intraoperative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Operatory Time	To assess if the use of Indocyanine Green cause a significant increase of the operatory time	Intraoperative
Complications	To assess if the use of Indocyanine Green increase the percentage of intra and post-operative complications	From operatory room up to 3 days
Side effects	Evaluation of possible side effects related to the use of Indocyanine Green as a fluorescent endometriosis' marker	From operatory room up to 3 days
Sensibility and Specificity of Near Infrared Vision with Indocyanine green in detection of endometriotic lesions	Optical qualitative assessment through the visual evaluation of a single expert surgeon (presence / absence of fluorescence, due to the injection of the Indocyanine Green and the use of the Near Infrared vision, at the level the of suspected endometriotic lesions)	Intraoperative

Collaborators and Investigators

• Sponsor: Catholic University of the Sacred Heart
• Investigators: Principal Investigator: Francesco Cosentino, MD, Fondazione di Ricerca e Cura Giovanni Paolo II , Campobasso , Italy

Publications and helpful links

General Publications

• Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9.
• Cosentino F, Vizzielli G, Turco LC, Fagotti A, Cianci S, Vargiu V, Zannoni GF, Ferrandina G, Scambia G. Near-Infrared Imaging with Indocyanine Green for Detection of Endometriosis Lesions (Gre-Endo Trial): A Pilot Study. J Minim Invasive Gynecol. 2018 Nov-Dec;25(7):1249-1254. doi: 10.1016/j.jmig.2018.02.023. Epub 2018 Mar 15.

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2016
• Primary Completion (Actual): May 19, 2019
• Study Completion (Actual): May 19, 2019

Study Registration Dates

• First Submitted: April 30, 2019
• First Submitted That Met QC Criteria: April 30, 2019
• First Posted (Actual): May 2, 2019

Study Record Updates

• Last Update Posted (Actual): August 5, 2020
• Last Update Submitted That Met QC Criteria: August 3, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: indocyanine Green; deep Infiltrating Endometriosis; near-Infrared Vision; occult endometriosis; invisible endometriosis
• Additional Relevant MeSH Terms: Endometriosis
• Other Study ID Numbers: 736513. A 287 / C.E./2013

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No