Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000828820p
Ethics application status
Submitted, not yet approved
Date submitted
26/04/2021
Date registered
29/06/2021
Date last updated
29/06/2021
Date data sharing statement initially provided
29/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Imaging technique to predict skin death during mastectomy and reconstruction surgery
Scientific title
The effect of indocyanine green angiography on postoperative mastectomy skin flap necrosis in breast reconstruction: The ICGA FLAP randomized controlled trial
Secondary ID [1] 304062 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 321703 0
Mastectomy skin flap necrosis 321704 0
Breast reconstruction 321705 0
Condition category
Condition code
Surgery 319445 319445 0 0
Surgical techniques
Cancer 319446 319446 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: Surgery WITH Indocyanine green Angiography

Materials:
Laparotomy sponges and staples
DRUG: Indocyanine green (ICG) supplied as a sterile water-soluble lypophilised power: Infracyanine® 25mg/10mL (SERB, Paris, France)
- strength: 25mg/mL
- dose: weight-dependent dosage: 2mL for patients weighing <50Kg, 3mL for patients weighing 50-100Kg, and 4mL for patients weighing over 100Kg
- duration: single Stat dose
- mode: intravenous injection
Normal saline: 10mL flush following administration of indocyanine green
Near-infrared light source from the SPY Elite System or SPY PHI (Novadaq Technologies Inc., Mississauga, Canada)

Procedures, activities, and/or processes used:
1. Skin- or nipple-sparing mastectomy
2. Clinical assessment of mastectomy skin flap perfusion by surgeon and first assistant: skin tissue colour, capillary refill, turgor, temperature and dermal edge bleeding
3. Placement of laparotomy sponges in breast pocket to fill dead space and allow skin flaps to lie flat without areas of redundancy or stretch
4. Temporary closure of skin with staples
5. Indocyanine green administered intravenously stat, at a weight dependent dosage, just after completion of mastectomy and prior to reconstruction
6. Operating room lights will be turned off
7. Excitation of fluorescence by near-infrared light source from the fluorescence imaging systems: SPY Elite System or SPY PHI (Novadaq Technologies Inc., Mississauga, Canada)
8. Video recording of perfusion for a total of 90 seconds after fluorescence is first detected in mastectomy skin. Bilateral cases will be recorded for bilateral cases, recorded with a single administration of indocyanine green (ICG) dye and snapshots will be taken of both breasts within 10 seconds of the 90-second time point
9. Analysis of skin flap vascularisation using perfusion maps and perfusion values obtained by SPY-Q software at the 90-second-point
10. Assessment of perfusion as “well perfused”, “adequately perfused”, “marginal” or “poorly perfused” using absolute (based off of a fixed greyscale that is consistent from image to image) and relative perfusion values.
11. Surgical decision regarding reconstruction to be made such as proceeding with breast reconstruction, delaying breast reconstruction or excising nonviable tissue
12. Completion of reconstruction
note: preoperative antibiotics and drains are used if indicated

Who: Surgeon and first assistant

Mode of delivery: Face to face, provided individually

Number of times: Single dose administration of indocyanine green

Duration: Angiography will video record perfusion for a total of 90 seconds after fluorescence is first detected in the mastectomy skin. Bilateral cases will be recorded with a single administration of indocyanine green (ICG) dye and snapshots will be taken of both breasts within 10 seconds of the 90-second time point.

Location: Operating theatres

Duration: Total duration of breast reconstruction is approximately 130minutes, with the intervention (indocyanine green administration, perfusion analyses and interpretation) adding approximately 10 minutes to the total surgical time

Monitoring of adherence: Adherence to the intervention will be followed by the use of laminated sheets with instructions on dosage and administration of Indocyanine Green, and examples of well and poorly perfused skin flaps for reference.
Intervention code [1] 320384 0
Treatment: Surgery
Intervention code [2] 320385 0
Prevention
Comparator / control treatment
Control: Surgery WITHOUT Indocyanine green Angiography

Procedures, activities, and/or processes used:
1. skin- or nipple-sparing mastectomy
2. clinical assessment of mastectomy skin flap perfusion by surgeon and first assistant: skin tissue colour, capillary refill, turgor, temperature and dermal edge bleeding
3. assessment of perfusion as “well perfused”, “adequately perfused”, “marginal” or “poorly perfused” using clinical judgement
4, surgical decision regarding reconstruction to be made such as proceeding with breast reconstruction, delaying breast reconstruction or excising nonviable tissue
note: preoperative antibiotics and drains are used if indicated

Who: surgeon and first assistant

Location: operating theatres

Duration: Total duration of the breast reconstruction without indocyanine green angiography is approximately 120 minutes
Control group
Active

Outcomes
Primary outcome [1] 327315 0
Mastectomy Skin Flap Necrosis rate:
- All-inclusive mastectomy skin flap necrosis including: epidermolysis, partial-thickness/superficial necrosis and full-thickness necrosis.
- Full-thickness necrosis is defined as a loss of epidermis and dermis with exposure of subcutaneous fat, muscle, acellular dermal matrix, or implant.
- Partial-thickness/superficial necrosis is defined as the loss of epidermis, partial dermal loss, and/or eschar formation that does not expose subcutaneous fat.

Necrosis will be diagnosed in the postoperative period including during the hospital admission, at outpatient clinic followups (at 7 days, 30 days and 90 days) and at any hospital readmissions. Necrosis will be diagnosed based on clinical examination by the registrar or fellow or consultant attending to the patient. Laminated sheets with example images of “epidermiolysis”, “partial-thickness/superficial” necrosis and “full-thickness” necrosis of mastectomy skin flaps including nipples will be available in each outpatient breast clinic for reference. All patients will be reviewed by the consultant to ensure a correct diagnosis of necrosis is made and that no cases of necrosis are missed.

The diagnosis of necrosis will also be conducted by a blinded assessor who is a consultant breast surgeon. The independent reviewer will not have knowledge of the exposure received. A photograph of the wound will be taken with patient consent. The image will be sent in a coded blinded fashion to the independent reviewer. The reviewer will assess the image for necrosis based on the definition that “necrosis” includes epidermolysis, partial-thickness/ superficial necrosis or full-thickness necrosis. Full-thickness necrosis is defined as a loss of epidermis and dermis with exposure of subcutaneous fat, muscle, acellular dermal matrix or implant. Partial-thickness/superficial necrosis is defined as the loss of epidermis, partial dermal loss, and/or eschar formation that does not expose subcutaneous fat.

This information will be documented and accessible through the patient's medical record.
Timepoint [1] 327315 0
90 days postoperative
Secondary outcome [1] 394582 0
Changes in the surgical strategy with intraoperative ICGA use including:
- Excision of nonviable tissue
- Reducing tissue expander volume
- Delaying reconstruction surgery
- Antibiotics
- Negative wound pressure therapy dressings

This information will be collected prospectively during the operation, hospital admission and at followup outpatient clinic visits. Changes in the surgical strategy with intraoperative ICGA use will be assessed by accessing operation reports and patient medical records
Timepoint [1] 394582 0
Intraoperative
Secondary outcome [2] 394584 0
Infection: Superficial, Deep or Organ space surgical site infection as defined by the Centres for Disease Control and Prevention (CDC).
Patients treated with oral or IV antibiotics will be documented, including patients who have loss of implant due to infection.

Rates of infection will be determined by clinician assessment during postoperative follow up in clinic at 7 days, 30 days and 90 days, where a wound infection will be diagnosed clinically based on the CDC definition. This information will be documented and accessible through the patient's medical record.
Timepoint [2] 394584 0
90 days postoperative
Secondary outcome [3] 394585 0
Seroma: Any evidence of a seroma will be documented based on requirement of a surgical intervention or non-surgical management.

Seromas will be will be determined by clinician assessment during postoperative follow up in clinic at 7 days, 30 days and 90 days, where a clinical examination and ultrasound may also be performed. This information will be documented and accessible through the patient's medical record.
Timepoint [3] 394585 0
90 days postoperative
Secondary outcome [4] 394586 0
Wound Dehiscence or implant extrusion (composite outcome): Wound breakdown and exposure of acellular dermal matrix and implant will be documented.

Wound Dehiscence or implant extrusion will be determined by clinician assessment during postoperative follow up in clinic at 7 days, 30 days and 90 days, where a clinical examination will also be performed. This information will be documented and accessible through the patient's medical record. Exposure of the acellular dermal matrix and implant extrusion secondary to wound dehiscence will also be documented.
Timepoint [4] 394586 0
90 days postoperative
Secondary outcome [5] 394587 0
Removal of Implant: Patients who require removal of their implants will be documented along with the cause for their loss of implant.

Removal of implant will be determined by clinician assessment during postoperative follow up in clinic at 7 days, 30 days and 90 days, where a clinical examination will also be performed. This information will be documented and accessible through the patient's medical record.
Timepoint [5] 394587 0
90 days postoperative
Secondary outcome [6] 394588 0
Readmission

Hospital readmission details will be assessed by accessing the patient's medical records.
Timepoint [6] 394588 0
12 months postoperative
Secondary outcome [7] 396242 0
Other complications

Other complications will be assessed by accessing the patient's medical records, which includes details regarding emergency presentations.
Timepoint [7] 396242 0
12 months postoperative
Secondary outcome [8] 396244 0
Haematoma: Any evidence of a haematoma will be documented based on requirement of a surgical intervention or non-surgical management.

Haematomas will be will be determined by clinician assessment during postoperative follow up in clinic at 7 days, 30 days and 90 days, where a clinical examination will also be performed. This information will be documented and accessible through the patient's medical record.
Timepoint [8] 396244 0
90 days postoperative

Eligibility
Key inclusion criteria
- Being scheduled for unilateral or bilateral nipple- or skin-sparing mastectomy (prophylactic or for the treatment of cancer) followed by breast construction
- Participant understands the study procedures and can provide informed consent to participate in the study
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
- Refusal to consent to participation in the study
- Participant has known contraindication to ICG injection, i.e., previous reaction to ICG
- Participant has Iodine allergy
- Participant has chronic kidney disease stage 3, 4, or 5
- Participant is pregnant

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation was concealed
A sealed envelope containing the randomization arm will be delivered after the patient provides written informed consent for participation. The envelope will be opened before the surgical procedure begins.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation into two arms was performed using a computerized random number generator list.
No stratification will be considered in the allocation process.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Power analysis yielded a study sample size of 478 patients to achieve 80% power to detect a difference between null hypothesis of 19% mastectomy skin flap necrosis in both groups and alternative hypothesis of 10% in the study group, with two-sided Chi-squared test and significance level of p = 0.05

Continuous variables will be reported as the mean (± standard deviation) if normally distributed, and median (range) if not normally distributed. Differences between means will be analysed using Student’s t test. Categorical variables will be analysed using the Chi-squared and Fisher’s exact tests. A p value < .05 will be considered significant. Statistical analysis will be performed with RStudio, version 1.4.1106.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/07/2021
Actual
Date of last participant enrolment
Anticipated
1/06/2023
Actual
Date of last data collection
Anticipated
1/06/2024
Actual
Sample size
Target
478
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 19193 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment postcode(s) [1] 33767 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 308443 0
Hospital
Name [1] 308443 0
Chris O’Brien Lifehouse
Country [1] 308443 0
Australia
Funding source category [2] 308448 0
Charities/Societies/Foundations
Name [2] 308448 0
Royal Australasian College of Surgeons
Country [2] 308448 0
Australia
Primary sponsor type
Hospital
Name
Chris O’Brien Lifehouse
Address
119-143 Missenden Road
Camperdown NSW 2050 Australia
Country
Australia
Secondary sponsor category [1] 309278 0
Charities/Societies/Foundations
Name [1] 309278 0
Royal Australasian College of Surgeons
Address [1] 309278 0
250-290 Spring Street
East Melbourne VIC 3002 Australia
Country [1] 309278 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 308401 0
Sydney Local Health District HREC - RPAH
Ethics committee address [1] 308401 0
Ethics committee country [1] 308401 0
Australia
Date submitted for ethics approval [1] 308401 0
27/04/2021
Approval date [1] 308401 0
Ethics approval number [1] 308401 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110590 0
Dr Chu Nguyen
Address 110590 0
Chris O’Brien Lifehouse
119-143 Missenden Road
Camperdown NSW 2050 Australia
Country 110590 0
Australia
Phone 110590 0
+61 401608581
Fax 110590 0
Email 110590 0
[email protected]
Contact person for public queries
Name 110591 0
Chu Nguyen
Address 110591 0
Chris O’Brien Lifehouse
119-143 Missenden Road
Camperdown NSW 2050 Australia
Country 110591 0
Australia
Phone 110591 0
+61 401608581
Fax 110591 0
Email 110591 0
[email protected]
Contact person for scientific queries
Name 110592 0
Chu Nguyen
Address 110592 0
Chris O’Brien Lifehouse
119-143 Missenden Road
Camperdown NSW 2050 Australia
Country 110592 0
Australia
Phone 110592 0
+61 401608581
Fax 110592 0
Email 110592 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Current supporting documents:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11484Study protocol  [email protected]
11485Statistical analysis plan  [email protected]
11486Informed consent form  [email protected]
11487Clinical study report  [email protected]
11488Ethical approval  [email protected]
11489Analytic code  [email protected]


Updated to:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11484Study protocol  [email protected]
11485Statistical analysis plan  [email protected]
11486Informed consent form  [email protected]
11487Clinical study report  [email protected]
11488Ethical approval  [email protected]
11489Analytic code  [email protected]
23754Ethical approval    381883-(Uploaded-29-10-2023-11-54-52)-Study-related document.pdf
23755Ethical approval    381883-(Uploaded-29-10-2023-11-54-53)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.