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Trial registered on ANZCTR


Registration number
ACTRN12617000132347
Ethics application status
Approved
Date submitted
18/01/2017
Date registered
24/01/2017
Date last updated
2/05/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The EXCISE Study - EXcisional treatment Comparison for In Situ Endocervical adenocarinoma
Scientific title
Excisional treatment in women with cervical adenocarcinoma-in-situ (AIS): a prospective randomised controlled non-inferiority trial to compare AIS persistence/recurrence after loop electrosurgical excision procedure to cold knife cone biopsy.
Secondary ID [1] 290929 0
None
Universal Trial Number (UTN)
Trial acronym
EXCISE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Adenocarcinoma in situ (AIS) of the uterine cervix 301652 0
Condition category
Condition code
Cancer 301362 301362 0 0
Cervical (cervix)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Eligible participants reported on screening cytology referred to a gynaecologist or gynaecological oncologist will be randomised to undergo a LEEP or CKC procedure.

Participants randomised to the Intervention arm LEEP, will have their procedure performed either under local or general anaesthesia in an outpatient setting or operating theatre at the discretion of the treating specialist as per local routine practice. All participants will undergo endocervical curettage at the time of their LEEP or CKC. The approximate duration of the procedure is 15 - 30 minutes.

Loop diathermy (LEEP) is the most commonly used treatment for high grade squamous dysplasia of the cervix in developed countries. The dimensions of the loop should be chosen after colposcopy preceding therapy to meet the width of the transformation zone and the planned type (length) of excision. Excisions are classified according to the length of cervix excised.
Type I - usually to 8 mm and not more than 10 mm length of cervical tissue excised
Type 2 - not more than 15 mm length of tissue excised
Type 3 - equivalent to ‘cone biopsy’ and > 15 mm length
In this Study only type 2 and 3 Excision are permitted.
Diathermy settings should be significantly higher than used in most open or laparoscopic surgeries to reduce thermal artefact (this should be minimised to 0.2 mm). It is imperative that the clinician obtain the recommended power settings from the electrosurgical system manufacturer. It should be noted that each clinician will have a personal preference (to suit their surgical technique, loop size, speed of excision and other factors) that determine their personal ‘best settings’ for electrosurgical procedures. Extensive application of coagulation current should be avoided, especially at the endocervical margin, which rarely bleeds. A single pass of the loop (side to side or posterior to anterior) to produce a specimen in one piece is optimal. LEEP may be performed in an operating theatre, outpatient clinic or consulting rooms under local or general anaesthesia in accordance with local practice and at the discretion of the treating specialist.

A cold knife cone biopsy uses a scalpel to excise a cone shaped piece of cervical tissue where the glandular abnormality (AIS) is located. The shape of the excision is not in reality a true cone, but a cone on top of a cylinder. The initial incision is perpendicular to the external cervical surface to ensure the excision of glands originally exposed in the post-menarche transformation zone now overlain by mature squamous metaplasia. Cone biopsies are type 3 excisions. The procedure is performed in an operating theatre under general anaesthesia by a gynaecological oncologist or gynaecologist with experience in the technique.


All treating Investigators will be highly experienced providers and certified under the Colposcopy Quality Improvement Program (CQUIP) in accordance with the requirements of the Royal Australian and New Zealand College of Obstetrics and Gynaecology.

Following treatment all patients will undergo the 'Test of Cure' management pathway.

* Colposcopy and cervical cytology at 6 months' post excisional treatment
* cervical cytology on oncongenic HPV typing at 12 month's post treatment and then annually in accordance with the revised NHMRC guidelines.
Intervention code [1] 296870 0
Treatment: Other
Intervention code [2] 296927 0
Treatment: Surgery
Comparator / control treatment
Cold knife cone biopsy (CKC).

A cold knife cone biopsy uses a scalpel to excise a cone shaped piece of cervical tissue where the glandular abnormality (AIS) is located. The shape of the excision is not in reality a true cone, but a cone on top of a cylinder. The initial incision is perpendicular to the external cervical surface to ensure the excision of glands originally exposed in the post-menarche transformation zone now overlain by mature squamous metaplasia. Cone biopsies are type 3 excisions. The procedure is performed in an operating theatre under general anaesthesia by a gynaecological oncologist or gynaecologist with experience in the technique. The approximate duration of the procedure is 30 - 45 minutes.
Control group
Active

Outcomes
Primary outcome [1] 300756 0
AIS histopathological margin status - either margins involved (positive margin) or margins not involved (negative margin)

Rationale: margin status has consistently been shown to predict persistence and recurrence of cervical AIS. Disruption to the excision specimen can make orientation and interpretation of tissue margins impossible. If there are significantly more LEEP specimens with positive margins compared to those excised by CKC, or if there are a greater number of specimens excised in more than one piece compared to CKC, then it may not be appropriate to conduct a larger phase III study.
Timepoint [1] 300756 0
Baseline (at the time of the procedure).
Primary outcome [2] 300813 0
Status of the excised specimen (single specimen or more than one piece).
Timepoint [2] 300813 0
Baseline (at the time of the procedure).
Secondary outcome [1] 330801 0
Frequency of post-operative infection assessed by review of the medical records.

Rationale: retrospective studies suggested that LEEP is associated with fewer early complications. Although the proposed study is underpowered to detect differences in these outcomes, the purpose of their inclusion is to determine the feasibility of data collection.
Timepoint [1] 330801 0
6 weeks post procedure
Secondary outcome [2] 330949 0
Frequency of secondary haemorrhage assesses by review of medical records.
Timepoint [2] 330949 0
6 weeks post procedure
Secondary outcome [3] 330950 0
Hospital readmission assessed by review of medical records.
Timepoint [3] 330950 0
6 weeks post procedure
Secondary outcome [4] 330951 0
Return to the operating theatre assessed by review of medical records.
Timepoint [4] 330951 0
6 weeks post procedure
Secondary outcome [5] 330952 0
Patient satisfaction assessed by using those aspects of the European Organization for Research and Treatment of Cancer in-patient satisfaction EORTC-OUTPATSAT-7 and EORTC-PATSAT-33 which will provide data in line with Section 7 and Section 12.
of the protocol.
Timepoint [5] 330952 0
6 weeks post procedure

Eligibility
Key inclusion criteria
1. Aged between > = 18 to < = 45 years of age at time of study enrolment.
2. Documentation of AIS on cervical cytology and/or cervical biopsy test results.
3. Lesion amendable to single pass excision (serial endocervical excisions including 'top-
hat' will not be permitted in accordance with American Society for Colposcopy and
Cervical Pathology Recommendations.
4. Proficient in English
Minimum age
18 Years
Maximum age
45 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. High-grade cervical abnormality prior to current AIS diagnosis.
2. Previous excisional or ablative treatment (LEEP, CKC, Fisher cone biopsy, laser cone).
3. Cytology suspicious of invasion.
4. Clinical/colposcopic suspicion of invasion.
5. Presence of a concurrent gynaecological cancer.
6. Patients unable to comply with follow-up evaluations.
7. Immunosuppression.
8. Pregnancy.
9. Lesion considered unsuitable for single pass excision by treating specialist.

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 phone/fax/computer

The allocation sequence will be implemented by central telephone (interactive voice response system).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (ie. computerised sequence generation).

Generation of the allocation sequence will be by computer generated random numbers
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
N/A
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Descriptive statistics will be used for the pilot study.
If the pilot study demonstrates safety and feasibilty then for the phase III study Kaplan-Meier and log rank tests will be utilised to test for non-inferiority at median follow-up of 5 years (with patient recruitment between 4-5 years. Proportional Hazard models will be utilised to test for differences between the two treatment groups controlling for confounding variables.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,WA,VIC
Recruitment hospital [1] 7324 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [2] 7325 0
The Royal Women's Hospital - Parkville
Recruitment hospital [3] 7326 0
Royal Hospital for Women - Randwick
Recruitment hospital [4] 7327 0
King Edward Memorial Hospital - Subiaco
Recruitment hospital [5] 7338 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 15099 0
6008 - Subiaco
Recruitment postcode(s) [2] 15100 0
3052 - Parkville
Recruitment postcode(s) [3] 15101 0
2031 - Randwick
Recruitment postcode(s) [4] 15124 0
2145 - Westmead
Recruitment outside Australia
Country [1] 8577 0
New Zealand
State/province [1] 8577 0
Auckland and Christchurch

Funding & Sponsors
Funding source category [1] 295345 0
Other Collaborative groups
Name [1] 295345 0
Australian and New Zealand Gynaecological Oncology Group (ANZGOG)
Address [1] 295345 0
119-143 Missenden Road,
CAMPERDOWN NSW 2050
Country [1] 295345 0
Australia
Primary sponsor type
Hospital
Name
St John of God Hospital, Subiaco WA 6008
Address
12 Salvado Road
Subiaco WA 6008
Country
Australia
Secondary sponsor category [1] 294170 0
None
Name [1] 294170 0
Address [1] 294170 0
Country [1] 294170 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296681 0
St John of God Health Care HREC
Ethics committee address [1] 296681 0
C/o St John of God Subiaco Hospital
12 Salvado Road
SUBIACO WA 60085
Ethics committee country [1] 296681 0
Australia
Date submitted for ethics approval [1] 296681 0
06/03/2017
Approval date [1] 296681 0
12/04/2017
Ethics approval number [1] 296681 0
TBA

Summary
Brief summary
The aim of this pilot study is to compare loop electrosurgical excision procedure to cold knife cone biopsy for treatment of adenocarcinoma in situ.

Who is it for?
You may be eligible to join this study if you are a woman aged between 18 and 45 years old and have been diagnosed with adenocarcinoma in situ (AIS) with lesions amenable to single pass excision.

Study details
AIS most frequently occurs in young women (less than 45 years of age) who may wish to preserve their fertility. If this is the case, there are two treatment options available: cold knife cone (CKC) biopsy or loop electrosurgical excisional procedure (LEEP).

In Australia, CKC is regarded as the 'gold standard' treatment for AIS. However, to date most AIS studies have been limited by small patient numbers and short follow-up periods. Further evidence is required to confirm if CKC is the superior treatment type for managing AIS.

Participants in this study are randomly allocated (by chance) to one of two groups. Participants in one group will have their lesions removed using LEEP, whilst participants in the other group will have their lesions removed using CKC.

Following treatment, all participants will undergo the 'Test of Cure' management pathway which includes follow-up examinations at 6 and 12 months post-treatment. Assessments for early complications and patient satisfaction will occur 6 weeks post-treatment.

We are hoping to perform a pilot research study to confirm the safety and feasibility of conducting a much larger clinical trial which would be the first to compare CKC and LEEP in this way. Study findings could potentially improve patients' experiences and alter treatment guidelines since potential advantages of LEEP include the avoidance of general anaesthesia, provision of treatment in an outpatient setting, lower morbidity and reduced rates of obstetric complications.
Trial website
TBA
Trial related presentations / publications
TBA
Public notes
TBA

Contacts
Principal investigator
Name 71750 0
Dr Paul Cohen
Address 71750 0
St John of God Hospital Subiaco
12 Salvado Road
SUBIACO WA 6008
Country 71750 0
Australia
Phone 71750 0
+61 8 9468 5188
Fax 71750 0
+61 8 9381 2006
Email 71750 0
paul.cohen@sjog.org.au
Contact person for public queries
Name 71751 0
Dr Paul Cohen
Address 71751 0
St John of God Hospital Subiaco
12 Salvado Road
SUBIACO WA 6008
Country 71751 0
Australia
Phone 71751 0
+61 8 9468 5188
Fax 71751 0
+61 8 9381 2006
Email 71751 0
paul.cohen@sjog.org.au
Contact person for scientific queries
Name 71752 0
Dr Paul Cohen
Address 71752 0
St John of God Hospital Subiaco
12 Salvado Road
SUBIACO WA 6008
Country 71752 0
Australia
Phone 71752 0
+61 8 9468 5188
Fax 71752 0
+61 8 9381 2006
Email 71752 0
paul.cohen@sjog.org.au

No data has been provided for results reporting
Summary results
Not applicable