Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001439730
Ethics application status
Approved
Date submitted
1/04/2022
Date registered
10/11/2022
Date last updated
10/11/2022
Date data sharing statement initially provided
10/11/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessing lymphatic drainage of the normal splenic flexure by single-photon emission computerised tomography (SPECT) technology – A feasibility study
Scientific title
Assessing lymphatic drainage of the splenic flexure by single-photon emission computerised tomography (SPECT) in healthy adults undergoing routine colonoscopy – A feasibility study
Secondary ID [1] 306690 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lymphatic drainage of the splenic flexure 325640 0
Condition category
Condition code
Cancer 322997 322997 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a research study looking to better understand how a specific portion of the colon functions. The aim of the study is to see how the colon situated in the left upper quarter of the abdomen, near the spleen (i.e., splenic flexure), manages to drain its tissue fluid (i.e., lymph). So far, lymphatic drainage of this part of the colon remains incompletely understood.

The study is being conducted within the Department of Colorectal Surgery at Concord Hospital, Sydney Local Health District (SLHD) by Dr Krishanth Naidu, under the supervision of A/Prof Matthew Rickard, A/Prof Robert Russo and Dr Kheng-Seong Ng.

A Participant Information Sheet (PIS) will inform participants about what is involved in the study and help them decide whether they wish to take part.

2. Study Procedures
The study procedure will take place within the Concord Repatriation General Hospital. Participants will be included into the study only if they have a normal colonoscopy.

During the test
Part 1
Once a normal colonoscopy is performed (standard of care), the area of interest (i.e., splenic flexure) is explored (research component). A special tracer (described below) is placed using the scope to trace the lymphatics.

Part 2
Single photon-emission computed tomography (SPECT) is a test that uses a special type of camera and a tracer (a radioactive substance in liquid form) to look at organs in the body. With this study, the tracer is injected into a small portion of the participant's colon that we are interested in (close to the spleen) to trace the lymph flow of the region. After that, in the Nuclear Medicine Department, a special camera records where the tracer has moved to. As part of the SPECT, participants are required to lie still in a scanner for at least 30 minutes.
After the SPECT scan, participants will complete their recovery, if indicated, and subsequently discharged home. Participants are advised not to drive or operate heavy machinery after their colonoscopy. A follow-up phone call will be made at 1,7 and 30 days from SPECT to understand how participants are going. This will be in the form of a very brief telephone questionnaire.

After the test
Most of the radioactive tracer leaves the body through the urine within a few hours after the SPECT scan. We advise participants to drink more fluids, after the SPECT scan to help flush the tracer from the body. The body breaks down the remaining tracer over the next few days.

Before the test
No extra preparation is required before the SPECT.

It is important that women participating in this study are not pregnant, breast-feeding or directly caring for young children (<5years old). Woman of child-bearing potential, may be required to perform a pregnancy (urine) test before enrolment in the study.

Time commitment
The total time commitment for this study is approximately 4 hours, not including the follow-up phone calls.

Participants agreeing to participate in this study, you will be directed to an online platform for completion of an electronic consent (e-consent) prior to participating. Future use of non-identifiable information may be used for research purposes. In this instance approval from the relevant Human Research Ethics Committee is required to access it and any identifiable data.

Description of intervention
1. Details of the colonoscopy:
A. As a standard of care, a complete colonoscopy (to investigate presenting symptoms/signs) is performed prior to dedicated interrogation of the splenic flexure (SF) with submucosal radio tracer. If lesions are noted that require biopsy, tattooing, clipping or other intervention, the participant is excluded from the study.
B. The standard of care colonoscopy will be performed by the treating clinician.
C. The apex of the SF is defined as the highest and most angulated point of the colon between the transverse colon and the descending colon, assessed visually by the investigator. This is further supported with a visual aid by way of a scope guide that defines the real time position of the scope. A Bluetooth® link is established between the scope guide transducer in the endoscope and the receiving screen. Furthermore, the architecture of the transverse colon compared to the descending and ascending colon, adds to localisation of the SF.

2. Radio tracer placement
A. Technetium-99 (Tc-99m) is reconstituted in the Nuclear Medicine Department with a nano colloid – Nanoscan (Media Radiopharma, Hungary). A Nanoscan vial contains 500mcg of nano colloidal human albumin. This is reconstituted with sodium pertechnetate (Tc-99m) solution for submucosal injection. 40MBq of Tc-99m reconstituted to 0.5ml will be injected. At colonoscopy Tc-99m nano-colloid will be injected through the standard colonoscopic working port.
B. A 23gauge (0.6mm diameter) 5mm Carr-Locke injection needle (Steris Endoscopy, Device Technologies, USA) is used for instillation of the radio isotope. This needle has automatic retraction technology to limit inadvertent needle stick and spillage. This needle is housed within a 2.5mm diameter sheath. The needle is attached to a 2300mm long conduit with a fixed volume of 1.38ml. This is important as it acknowledges not only the volume of tracer to be used for luminal priming but the volume of 0.9% NaCl follow-through required following tracer administration to optimise tracer delivery and deposition.
C. 0.5ml of Tc-99m nano colloid reconstituted into 1.4mls is to be injected in the submucosal plane. Injection of this volume should not impede lymphatic flow.
D. After endoscopic SF localization, correct needle placement is confirmed by raising a submucosal bleb with Tc-99m directly followed by injection of the remainder of the Tc-99m. The system is flushed with 1.4 mL NaCl 0.9% post Tc-99m instillation to achieve maximal tracer administration and limit colonoscope radioactivity.
E. Crucially, the time of injection is recorded.
F. Injection of Tc-99m following localisation of the SF at the completion of the standard of care colonoscopy will add further 10 mins to the procedure time of approximately 30 minutes.
G. The tracer will be injected by Dr Krishanth Naidu.
H. A resolution clip is deployed at the site of infiltration as a further marker of SF identification on radiographic imaging.

3. Post- radio tracer placement
A. The participant is nursed within the confines of the endoscopy or operating theatre recovery suite with appropriate recovery precautions. Note is also made of reaction symptoms and signs, if any.
B. The nuclear medicine imaging suite is notified of the participants post-injection status.
C. The participant is suitably recovered prior to being transferred to the imaging suite for the SPECT-CT scan.
D. The colonoscope is submitted for appropriate cleaning and sterilization.

4. Details of SPECT-CT imaging:
A. Imaging acquisition at 1 hour following Tc-99m administration is aimed for.
B. Participant is assisted across to the gamma scanner bed
C. Time immediately prior to the commencement of the scan is recorded.
D. Dosage and radioactivity of Tc-99m is recorded in the SPECT-CT report.
E. The SPECT-CT scan will be performed under the direction of A/Prof Rob Russo ( Nuclear Medicine Physician).

5. Conclusion of visit
A. At the conclusion of the scan, participants are discharged to their residences, in accordance with standard post-endoscopic recovery and nuclear medicine protocol.
B. Formal discharge from the hospital is from the Nuclear Medicine Department. This will mirror the standard discussion plans and discussions had with a patient who has had a diagnostic scintigraphy procedure within the department. The CI (Krishanth Naidu) will be in attendance all the way through the participant’s journey to address any questions.
C. Approximately 6 hours after the injection, the radioactive tracer will be nearly all removed from your body. We would advise against caring for young children within 6 hours of the radiotracer injection. No other restrictions are necessary following discharge.
D. An investigator review (Dr Krishanth Naidu) via a follow-up phone call on Day 1, 7 and 30 from SPECT-CT completion is planned. This is to assess for delayed post-colonoscopy complications and adverse reactions. It also establishes further rapport with the research team and allows the opportunity to address concerns or issues faced by participant through the stages of participation.
Intervention code [1] 323137 0
Diagnosis / Prognosis
Intervention code [2] 324600 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 330771 0
Feasibility of using an endoscopically placed submucosal radio-nuclide tracer, with subsequent scintigraphy mapping using SPECT-CT technology. This will be assessed by examining or confirming:
1. Time taken for research phase of colonoscopy (using the "intubation timer" that is built in to the endoscopy operating system)
2. Submucosal instillation of the radio tracer with minimal to no spillage intraluminally (via visual inspection by researcher and confirmation on subsequent SPECT CT imaging.
3. Participant recruitment and attrition rate (via an audit of study enrolment/withdrawal logs)
4. Protocol retention rate (via an audit of study protocol diary logs)
5. Time to SPECT CT after recovery from endoscopy procedure ( via a digital stopwatch)

All measures will be assessed together as a composite primary outcome.
Timepoint [1] 330771 0
From recruitment date to day-30 following research phase of colonoscopy, instillation of radio tracer and subsequent SPECT-CT. This thus encompasses the recruitment phase, research colonoscopy phase, SPECT-CT phase and follow up phase (Day 1, Day 7 and Day 30 phone calls).
Primary outcome [2] 332989 0
Safety profile of in vivo, endoscopically placed submucosal radio-nuclide tracer, with subsequent scintigraphy mapping using SPECT-CT technology with understanding and recording of adverse reaction profile and rate. This will be assess using a study specific questionnaire via a telephone call. A clinical examination will be undertaken if clinically warranted.

Examples of known/possible adverse events include but not limited to:
1. SPECT-CT related
a. Claustrophobia in individuals with a history of anxiety in closed spaces
b. This research study involves exposure to a small amount of radiation. As part of everyday living, everyone is exposed to naturally occurring background radiation and receives a dose of about 2 millisieverts (mSv) each year. The effective dose from this study is about 3mSv and is markedly less than a multiphase CT abdomen and pelvis (~30mSv), which is regularly requested in the hospital and community setting. At the dose level used in our study, no harmful effects of radiation have been demonstrated as any effect is too small to measure. The radiation related risk is believed to be low and theoretically is less than 1 in 1000.
c. Reaction to contrast is rare but may involve:
i. Allergic reaction (e.g., rash, wheeze, difficulty breathing, fever, chest pain)
d. Per-rectal bleeding from submucosal injection

2. Colonoscopy related
a. Hole in bowel (Perforation)
i. Less than 1 in 1000 risk
b. Increased anaesthetic time
i. Slightly longer sedation time (Not expected to affect recovery time and discharge)
c. Placement of clip
i. Too deep (very rare) – causing perforation
ii. Bleeding (rare)
iii. Clip falls off
d. Pain
e. Tracer placed in an unintended layer of bowel (too deep or too shallow)
Timepoint [2] 332989 0
24hours, 7 days and 30 days following radio tracer injection and SPECT CT acquisition
Secondary outcome [1] 415454 0
Quantify the splenic drainage patterns using volumes of interest (VOI) tools that is an inherent SPECT-CT capability. All participants with image acquisition within 2 hours of radiotracer injection are considered for quantitative analysis.
Timepoint [1] 415454 0
1 hour, 2 hour and 4 hour post tracer injection using a SPECT scanner

Eligibility
Key inclusion criteria
Participants who have had a standard of care colonoscopy with normal findings and no intervention performed.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. <18 years old
2. Women lactating, pregnant, or of childbearing potential who are not willing to avoid becoming pregnant during the study.
3. Participants unable to avoid caring for young children for a minimum of 6-hours post radio tracer injection.
4. Participants with a history of colorectal surgery requiring resections.
5. Participants with a history of discontinuous colon and colostomy formation.
6. Participants undergoing an emergency colonoscopy.
7. Participants who may have any disease process that could distort the normal lymphatic drainage of the SF.
8. Participants undergoing an intervention during the colonoscopy.
9. Participants who lack capacity to provide informed consent or understand the study requirements.
10. Allergy to radio tracer or its associated constituents.
11. Participants with a history of claustrophobia.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The dominant lymphatic pedicle is defined by focal tracer accumulation within the mesocolon corresponding to one of the named mesenteric arterial pedicles.

Volumes of interest (VOI) will be used to delineate the amount of radioactivity for pharmacokinetics. The dominant drainage direction will be defined at 60mins post-radio tracer submucosal injection.

Only descriptive statistics will be analysed.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
16/11/2022
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
5
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 21977 0
Concord Repatriation Hospital - Concord
Recruitment postcode(s) [1] 37076 0
2139 - Concord

Funding & Sponsors
Funding source category [1] 311021 0
Hospital
Name [1] 311021 0
Concord Repatriation General Hospital
Country [1] 311021 0
Australia
Primary sponsor type
Hospital
Name
Concord Repatriation General Hospital
Address
Concord Institute of Academic Surgery
Concord Repatriation General Hospital
Building 20, Level 1
Hospital Road
Concord
NSW
2139
Australia
Country
Australia
Secondary sponsor category [1] 312508 0
None
Name [1] 312508 0
Address [1] 312508 0
Country [1] 312508 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310568 0
Sydney Local Health District HREC - Concord Repatriation General Hospital
Ethics committee address [1] 310568 0
Sydney Local Health District
Human Research Ethics Committee
Concord Repatriation General Hospital
Building 20, Hospital Road
Concord NSW 2139
Ethics committee country [1] 310568 0
Australia
Date submitted for ethics approval [1] 310568 0
22/03/2022
Approval date [1] 310568 0
12/04/2022
Ethics approval number [1] 310568 0
2022/ETH00410

Summary
Brief summary
This study aims to assess the feasibility and safety of using a novel technique (i.e. radio-nuclide tracer [radioactive dye] that is injected directly into the bowel during a routine colonoscopy) to understand how a specific portion of the colon functions. The aim of the study is to see how the colon situated in the left upper quarter of your abdomen, near the spleen (i.e., splenic flexure) manages to drain its tissue fluid (i.e., lymph). So far, lymphatic drainage of this part of the colon remains incompletely understood.

Who is it for?
You may be eligible for this study if you are aged 18 years or older, you have been scheduled for a standard care colonoscopy (i.e. to investigate the reason for presentation to a surgeon), and are in good general health without a clinically significant medical history. People who have been diagnosed with colon or rectal cancer will not be eligible for this study.

Study details
All participants who choose to enrol in this study will undergo a standard colonoscopy procedure. As part of this study, participants will have a small volume of a radioactive tracer injected into their colon (large intestine) for additional imaging. The research phase of the colonoscopy and injection is anticipated to take 15 minutes. Within one to two hours after the injection has been made, participants will then be taken to the SPECT-CT scanner to have additional images taken of their bowel. This imaging procedure is anticipated to take one hour. Participants will be able to return home after the SPECT-CT. A study investigator will then contact all participants via phone call at 1 day, 7 days and 30 days after the imaging procedures to check on their health and determine any potential side effects of the injection.

It is hoped this research will contribute to our knowledge, insight and understanding of the lymphatic drainage of the healthy (non-cancerous) splenic flexure, using the most practical method available. Having knowledge of lymphatic drainage in healthy splenic flexures, we can then then explore the lymphatic drainage in individuals with cancer in the splenic flexure in future studies. We hope that these future studies will also improve understanding and optimise surgical management of splenic flexure cancers, leading to improved outcomes for these patients.
Trial website
Trial related presentations / publications
Public notes
As this is a pilot study, a proof of concept and scientific applicability needs validation prior to full appreciation of study limitations. Also, as a pilot study, the benefit to enrolled participants is minimal. However, this research undertaking has the capacity to benefit the larger surgical fraternity with a principal focus on future patients with colorectal cancer at the splenic flexure. Surgical management of cancer in this region of the colon has been contentious owing to the varied lymphatic drainage. This pilot trial is intended to equip us with knowledge, insight and understanding on the lymphatic drainage of the non-pathological splenic flexure, using the most physiological means possible. Armed with the knowledge of lymphatic drainage in non-pathological splenic flexures, we can then then explore the lymphatic drainage in individuals with cancer in the splenic flexure, with future studies. The latter will improve understanding and optimise surgical management of the highly controversial splenic flexure cancers. It is important to note that, the trial study population was not intended to include individuals with splenic flexure cancer as (i) the recruitment period will be lengthy owing to a 25-year incidence of 6% (CRGH unpublished data), (ii) the presence of cancer has the potential to alter the flow of lymphatics owing to a mass effect and (iii), given the lack of feasibility and safety on this preoperative technique, the investigators believe that subjecting a patient with a cancer diagnosis is unsafe from a psychological and oncological point of view. ii. Inability to control for radio tracer carriage via haematogenous route when submucosal bleb raised. iii. We acknowledge that participants will not have the opportunity between their standard of care colonoscopy and the research study to provide consent. However, this is the most pragmatic approach to running our study as participants and clinical departments would otherwise be faced with logistical challenges with need for multiple anaesthetics episodes and bowel preparation regimes. iv. Issue pertaining to identification of incidental findings is addressed by acknowledging that the use of SPECT-CT imaging is purely for the purposes of identifying lymphatic drainage of the SF. No diagnostic comments are made as nuclear medicine physicians are not radiologists and provide descriptions on radio tracer activity only. v. Patients of investigators (Dr Kheng-Seong Ng and A/Prof Matthew Rickard) will not be approached for participation in the study in view of perceived recruitment bias for the research phase of the colonoscopy. vi. The aim is to capture SPECT-CT image acquisition at 60-mins following Tc-99m injection. However, all participants with scans within 2 hours of injection will be considered. Data interpretation will depend upon actual time and image acquisition.

Contacts
Principal investigator
Name 118118 0
Dr Kheng-Seong Ng
Address 118118 0
Concord Institute of Academic Surgery
Concord Repatriation General Hospital
Building 20, Level 1
Hospital Road
NSW
2139
Australia
Country 118118 0
Australia
Phone 118118 0
+61 2 9767 9992
Fax 118118 0
Email 118118 0
k.s.ng@sydney.edu.au
Contact person for public queries
Name 118119 0
Dr Krishanth Naidu
Address 118119 0
Concord Institute of Academic Surgery
Concord Repatriation General Hospital
Building 20, Level 1
Hospital Road
NSW
2139
Australia
Country 118119 0
Australia
Phone 118119 0
+61 2 9767 9992
Fax 118119 0
Email 118119 0
krishanth.naidu@health.nsw.gov.au
Contact person for scientific queries
Name 118120 0
Dr Kheng-Seong Ng
Address 118120 0
Concord Institute of Academic Surgery
Concord Repatriation General Hospital
Building 20, Level 1
Hospital Road
NSW
2139
Australia
Country 118120 0
Australia
Phone 118120 0
+61 2 9767 9992
Fax 118120 0
Email 118120 0
k.s.ng@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data will be collectively analysed and presented as a cohort analysis.


What supporting documents are/will be available?

No Supporting Document Provided



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.