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Trial registered on ANZCTR


Registration number
ACTRN12623000950662
Ethics application status
Approved
Date submitted
2/08/2023
Date registered
4/09/2023
Date last updated
18/08/2024
Date data sharing statement initially provided
4/09/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of intraoperative warmed, humidified carbon dioxide insufflation in open laparotomy colorectal surgery patients undergoing Cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS HIPEC): a randomized controlled trial (Second WHCO2 trial)
Scientific title
Effect of intraoperative warmed, humidified carbon dioxide insufflation in open laparotomy colorectal surgery on 5-year survival rates of patients undergoing Cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS HIPEC): a randomized controlled trial (Second WHCO2 trial)
Secondary ID [1] 310208 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
WHCO2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Colorectal cancer 330884 0
Peritoneal Metastases 331089 0
Condition category
Condition code
Cancer 327672 327672 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients in the intervention group will receive warmed (37°C), humidified (98% RH) carbon dioxide. The delivered gas will be defined by the United States Pharmacopeia and National Formulary, which requires impurity of less than 200 parts per million, including water vapour.
The gas diffuser will be positioned inside the open abdominal wound cavity (in the epigastric region) at a depth of approximately 4cm from the skin as soon as the abdominal wall retraction has been done. The insufflation of warm humidified CO2 will then start and continue until the abdominal wall retractors are removed and closure of the abdominal wall is commenced (approx. a few hours). The intervention will be delivered by the anaesthesiologist and operation reports will be monitored to ensure consistency in administration of intervention. This medical grade CO2 will be warmed to 37°C and humidified to 98% RH using a humidification system. The HUMIGARD system kits are individually packaged in a sterile manner.
Intervention code [1] 326596 0
Treatment: Other
Comparator / control treatment
Patients in the control group will receive no gas insufflation into the open laparotomy wound. This is the current standard practice for all patients undergoing open laparotomy for colorectal resection.
Control group
Active

Outcomes
Primary outcome [1] 335473 0
The primary outcome of interest is the 5-year overall survival /disease free survival. Disease free status will be monitored by regular intervals of colonoscopy, CT scans and tumour marker levels. These are composite primary outcomes.
Timepoint [1] 335473 0
Colonoscopies to be done at 1 year and 4 years post surgery, CT scans will be done at 6 monthly intervals till year 3 then yearly thereafter to 5 years post surgery and tumour markers (CEA, CA19.9 and CA125) will be assessed 3 monthly till year 3, then 6 monthly thereafter until 5 years post surgery.
Primary outcome [2] 335476 0
Peritoneal damage will be assessed using various methods and be used to see if there is a correlation between survival and the peritoneal damage. Peritoneum will examined by light microscopy following staining with Haematoxylin and Eosin (H&E). Levels of inflammatory cytokines and chemokines will measured using a commercial ELISA kit. To assess oxidative peritoneal protein damage, the level of 3-chlorotyrosine and total native tyrosine in the peritoneal homogenates will be measured using high-pressure liquid chromatography with mass spectrometry (HPLC-MS). Also using immunohistochemistry, antibodies against MDA and other lipid oxidation products will be measured. Cell-apoptosis will be measured by the detection of active caspase-3/7 bioluminescence assayed in the stored tissue homogenates with Casapse-Glo® 3/7 Assay. A second marker of cell viability will be determined using the DeadEndTM Fluorometric TUNEL System. The extent of DNA fragmentation will be quantified through the measurement of green fluorescence intensity with a fluorescence microscopy.

These outcomes will be assessed as a composite primary outcome.
Timepoint [2] 335476 0
These will be measured from samples taken intraoperatively.
Secondary outcome [1] 424782 0
The secondary outcome of interest is the return of bowel function (flatus, stool) as documented in medical records.
Timepoint [1] 424782 0
Post-operative, at 30 days and 90 days
Secondary outcome [2] 425343 0
Commencement of diet (clear fluid, light diet, full diet) and duration of total parenteral nutrition. These are composite secondary outcomes, which will all be assessed during regular clinician visits and will be documented in electronical medical records.
Timepoint [2] 425343 0
Post-operative, at 30 days and 90 days
Secondary outcome [3] 425344 0
Hospital length of stay, this will be assessed in medical records.
Timepoint [3] 425344 0
Will be calculated from admission for operation only until hospital discharge.
Secondary outcome [4] 425345 0
Complications including prolonged postoperative ileus (failure to eat, pass flatus or evacuate bowel for more than 5 days), post operative wound infection, anastomotic breakdown, and Clavien Dindo III/IV/V complications. This will be assessed during clinical exams and recorded in electronic medical records.
Timepoint [4] 425345 0
During postoperative admission
Secondary outcome [5] 425346 0
30 day and 90 day mortality
Timepoint [5] 425346 0
30 and 90 days post surgery.
Secondary outcome [6] 425347 0
Unexpected readmissions. this will be documented in electronical medical records.
Timepoint [6] 425347 0
Whenever patient is readmitted post-operatively, from discharge until 5 years post surgery.

Eligibility
Key inclusion criteria
Colorectal adenocarcinoma peritoneal metastases confirmed on biopsy at time of diagnostic laparoscopy, Peritoneal cancer index score (diagnostic laparoscopic) <15, Intention to achieve Completeness of cytoreduction score (CCR) of 0. Willingness to provide informed consent and willingness to participate and comply with the study requirements.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Extraperitoneal metastasis (current),
Liver metastases,
Non-colorectal adenocarcinoma,
Inability to achieve CCR0,
Inoperable peritoneal carcinomatosis ,
PCI on diagnostic laparoscopy of more than 15,
During laparotomy for CRS/HIPEC, two surgeons agree and decide tumour spread is so advanced that proceeding with operation is futile or too dangerous (however will be analysed as intention to treat),
ECOG score >2,
Charlson Comorbidity index more than 8,
PCI (diagnostic laparoscopic)>16

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)
Central randomisation by REDcap database, managed by research officer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (computerised sequence generation)
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
Data will be analysed using IBM SPSS version 23 (New York, USA) and GraphPad Prism version 7.0 (GraphPad Software Inc, California, USA). Continuous variables will be tested using the D’Agostino-Pearson test. WHCO2 and Control groups will be compared using t-test/2 way ANOVA using Tukey’s multiple comparison test for parametric continuous variable and Mann-Whitney U test for the non-parametric continuous variables. To compare 5 year survival (overall survival, disease free survival), log-rank test will be used. The level of significance for all tests will be set at p< 0.05.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
11/09/2023
Actual
9/11/2023
Date of last participant enrolment
Anticipated
26/06/2025
Actual
Date of last data collection
Anticipated
31/12/2025
Actual
Sample size
Target
60
Accrual to date
8
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 25309 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 40985 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 314374 0
Other Collaborative groups
Name [1] 314374 0
Royal Australian College of Surgeons
Country [1] 314374 0
Australia
Funding source category [2] 314482 0
Charities/Societies/Foundations
Name [2] 314482 0
Colorectal Surgical Society of Australia & New Zealand
Country [2] 314482 0
Australia
Funding source category [3] 314483 0
Charities/Societies/Foundations
Name [3] 314483 0
Avant Scholarship
Country [3] 314483 0
Australia
Primary sponsor type
Government body
Name
Sydney Local Health District
Address
Level 11, King George V Building
Missenden Road
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 316435 0
None
Name [1] 316435 0
None
Address [1] 316435 0
None
Country [1] 316435 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313467 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 313467 0
Level 11, KGV Building Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 313467 0
Australia
Date submitted for ethics approval [1] 313467 0
19/09/2019
Approval date [1] 313467 0
04/12/2019
Ethics approval number [1] 313467 0
2019/ETH09802

Summary
Brief summary
This study aims to determine whether the use of warmed, humidified CO2 to protect the internal membranes within the lower abdomen in patients with peritoneal metastases from colorectal cancer, who are undergoing surgery and internally delivered focussed chemotherapy can reduce the recurrence of abdominal metastases and impact 5 year survival rates.

Who is it for?
You may be eligible for this study if you are an adult aged between 18 and 70 years of age, you have been diagnosed with colorectal cancer that has spread (metastastised) to other areas within your abdomen and you are eligible to undergo a combined surgical removal and internally delivered chemotherapy procedure called cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Study details
Participants who choose to enrol in this study will be randomly assigned by chance (similar to flipping a coin) to one of two treatment groups. Both groups will undergo the surgical procedure and internally delivered chemotherapy, but one group will also have warmed humidified CO2 gas applied to their internal membranes during the surgery. It is not anticipated that use of the CO2 will extend the duration of the surgery. Participants in both groups will also have tissue samples taken during the surgery for further analysis and will be asked to consent to their health information being accessed by the study team for up to 5 years after the surgery. Participants in both groups will also be asked to attend regular colonoscopies, CT scans and blood tests at regular intervals after the surgery, as per standard care for patients with this type of cancer.

It is hoped this research will determine whether use of warmed humidified CO2 during cancer removal surgery has an impact on the future spread of cancer within the abdomen and whether this technique has any impact on 5 year survival rates for patients with metastatic colorectal cancer.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 128266 0
A/Prof Cherry Koh
Address 128266 0
RPAH Medical Centre, 7/100 Carillon Ave, Newtown NSW 2042
Country 128266 0
Australia
Phone 128266 0
+61 2 9519 0064
Fax 128266 0
Email 128266 0
[email protected]
Contact person for public queries
Name 128267 0
Sascha Karunaratne
Address 128267 0
Royal Prince Alfred Hospital, Level 9, Building, 89 Missenden Rd, Camperdown NSW 2050
Country 128267 0
Australia
Phone 128267 0
+61 295153464
Fax 128267 0
Email 128267 0
[email protected]
Contact person for scientific queries
Name 128268 0
Cherry Koh
Address 128268 0
RPAH Medical Centre, 7/100 Carillon Ave, Newtown NSW 2042
Country 128268 0
Australia
Phone 128268 0
+61 2 9519 0064
Fax 128268 0
Email 128268 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Any de-identified data for studies approved both by the Chief Investigator of this study (A/Prof Cherry Koh) and a NHRMC approved HREC, will be shared.
When will data be available (start and end dates)?
Data will only be available post publication of all studies relating to the primary and secondary aims of this study in a peer-reviewed journal. It will be at the discretion of the Chief Investigator (A/Prof Cherry Koh) when this has been achieved. Data will be available in this way up to 5 years after the closure of the study, after which it will be destroyed as per protocol.
Available to whom?
Based on explicit consent from individual participants, de-identified individual patient data will be made available to researchers who comply with all regulations stipulated by a NHMRC approved Human Research Ethics Committee (HREC). Further, express written approval from Chief Investigator (A/Prof Cherry Koh) will be required (as per Research Data Management Plan).
Available for what types of analyses?
At the discretion of both the Chief Investigator (A/Prof Cherry Koh) and a NHRMC approved HREC, data will be made available for any approved analyses.
How or where can data be obtained?
A request to the Chief Investigator (A/Prof Cherry Koh; [email protected]) or Study Contact (Ms Solanki; [email protected]) will be required. From here and consistent with the above and explicit data sharing policy in the Research Data Management Plan, a process of transfer stipulated by a NHRMC approved HREC will be followed on a case by case basis.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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