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Trial registered on ANZCTR


Registration number
ACTRN12617000930381
Ethics application status
Approved
Date submitted
1/06/2017
Date registered
27/06/2017
Date last updated
28/10/2019
Date data sharing statement initially provided
23/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Observational management of young women under the age of 25 with cervical intraepithelial neoplasia (CIN3)
Scientific title
A prospective multicentre trial of observational management of CIN3 in women under the age of 25: safety and rate of spontaneous regression
Secondary ID [1] 292100 0
Nil
Universal Trial Number (UTN)
U1111-1197-2845
Trial acronym
CIN3MA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cervical Intraepithelial Neoplasia (CIN) 3 303521 0
Condition category
Condition code
Cancer 302932 302932 0 0
Cervical (cervix)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Observational management of Cervical Intraepthelial Neoplasia (CIN) grade 3 in women aged under 25 years for 12 months i.e., 6-monthly colposcopy examination with a directed cervical biopsy (histology), and cervical smear (cytology) undertaken by a trained colposcopist at a hospital-based colposcopy clinic for a total of 1 year (or until the woman turns 25 years old, whichever is sooner).

Attention will be paid to ensure the whole transformation zone and lesion are seen and that there is no colposcopic evidence of glandular or invasive disease. If a lesion persists, representative biopsies must be taken, two if possible and one from each quadrant in larger lesions. If the colposcopy is normal, we encourage the taking of a biopsy from the transformation zone in the previously affected area.

Treatment is indicated if the patient becomes symptomatic, there is colposcopic or cytological suspicion of invasive or glandular disease, the colposcopy is unsatisfactory and abnormal cytology persists, the histology is reported as invasive or glandular disease, the patient requests treatment, turns 25 years old without demonstrating persistent regression, or is unable to attend further follow up and the lesion persists. If treatment is performed a trial Completion Form is filled in and the patient subsequently managed as per normal practice.

If CIN2 or 3 persists, or cytology is reported as ASCH or HSIL, colposcopy should be repeated at 6 monthly intervals for 1 year. If CIN2 or 3, or ASCH or HSIL cytology persists, at this point, the patient should be treated. At this point, a trial Completion form is filled in.

Regression is:
- normal colposcopy, normal/low grade cytology, no biopsy taken OR
- normal colposcopy, normal/low grade cytology, normal/low grade histology OR
- low grade colposcopy, normal/low grade cytology, normal/low grade histology OR
- CIN 2 colposcopy but normal/low grade cytology, normal/low grade histology

Regression is not confirmed:
- CIN 3 colposcopy but normal/low grade cytology, normal/low grade histology
- if a lesion is present and a biopsy not taken
- if cytology is ASCH or worse or
- a smear is not taken or unsatisfactory

If regression is documented women must have a follow-up at 6 months with;
- a repeat colposcopy and smear and
- a biopsy if a lesion is present

If following the repeat colposcopy, criteria for regression is again met, the lesion has demonstrated persistent regression.

Following persistent regression and after discussion between the colposcopist and the woman, the patient may be discharged from the colposcopy clinic. If this is the case, a trial Completion Form is filled and follow-up is then as per National Cervical Screening Programme (NCSP) guidelines following high grade abnormality with a smear in 6 months (by primary smear taker). If the woman is not discharged from colposcopy clinic, a repeat colposcopy occurs at 6-12 months. Management should be based on the NCSP guidelines.

If regression is demonstrated at the 12 month follow up for the first time, the colposcopist will discuss either immediate treatment or follow up at 6 months. However at this point, a trial Completion form will be filled in, and the patient subsequent management should be based on the results of this colposcopy and the NCSP guidelines.

If following apparent regression, at the next follow up CIN2 or worse is seen or cytology is reported as ASCH or worse, 6 monthly follow up must continue unless the woman elects to be treated or continues on the trial protocol.
Intervention code [1] 298243 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 302327 0
Proportion of participants whose lesions regress to CIN1 or less.

Regression is defined as return to normal/low grade cytology and histology, and persistent regression is defined as regression on two or more successive 6 monthly visits.
Timepoint [1] 302327 0
Every 6 months for 12 months
Primary outcome [2] 302328 0
Proportion of participants who progress to microinvasive or invasive cancer.

Cervical cancer is staged by the International Federation of Gynecology and Obstetrics (FIGO) staging system. Microinvasive cancer (also known as Stage 1A) is a lesion in which neoplastic cells invade the stroma, in one or more sites, with a maximum depth of 5.0 mm below the base of the epithelium and maximum width of 7.0 mm, without lymphatic or blood vessel involvement. The depth of invasion should be measured from the base of the epithelium, either surface or glandular, from which it originates. Microinvasive cancer (stage IA) can be further subdivided into stages 1A1 and 1A2. Stage 1A1 encompasses stromal invasion <3.0 mm in depth and <7.0 mm in width, while stage 1A2 encompasses stromal invasion >3.0–5.0 mm in depth and <7.0 mm in width.

Invasive cancer (>Stage 1A) is a lesion in which neoplastic cells invade the stroma with a depth greater than 5.0 mm.
Timepoint [2] 302328 0
Every 6 months for 12 months
Primary outcome [3] 302329 0
Proportion of participants who require treatment (by review of medical records)
Timepoint [3] 302329 0
Every 6 months for 12 months
Secondary outcome [1] 335496 0
Proportion of participants who are lost to follow up (greater than 9 months)
Timepoint [1] 335496 0
Every 6 months for 12 months
Secondary outcome [2] 335497 0
Proportion of eligible women <25 years with CIN3 included in the trial (and reasons for exclusion) - this is a composite outcome
Timepoint [2] 335497 0
At the end of the recruitment period

Eligibility
Key inclusion criteria
- Age under 25 at date of initial biopsy.
- Attending colposcopy clinic as a result of an abnormal smear but without a history of prior high grade abnormality.
- Biopsy proven CIN3 (or CIN2/3).
- Entire lesion accessible to colposcopy.
- Participants in trial agree to six monthly colposcopy and cervical smear and biopsy for a total of two years.
- Cytology and pathology reviewed and CIN3 confirmed at a multidisciplinary meeting and no other clinical factor was identified that would exclude them from the trial.
- Signed informed consent
Minimum age
15 Years
Maximum age
24 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
- High grade cytological or histological abnormality prior to this referral.
- Unsatisfactory colposcopy.
- Large complex colposcopic abnormality where adequate histological sampling difficult.
- Cytology suspicious of invasion or glandular abnormality.
- Patients unwilling or unable to attend follow up.
- Patients whose cytology and histology have not been reviewed at MDM.
- Clinical suspicion of invasion or AIS.
- Any glandular histological or cytological abnormality.
- Concern on behalf of treating doctor that patient is unlikely to attend follow up.
- Immunosuppression.
- Pregnancy
- Post-coital bleeding or any other irregular vaginal bleeding not attributable to oral contraceptive related break through bleeding

Study design
Purpose of the study
Treatment
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
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
The pilot study objective is to provide clinically relevant information on the safety and practicality of observational management of CIN3 from a prospective 2-centre trial.
The primary aims of the pilot study are to document over 12 months, for a cohort of n=50 women under the age of 25 with a diagnosis of CIN3;
- Safety of delayed identification and treatment of CIN3 in young women,
- Recruitment rate, and
- Spontaneous rate of regression.
Data analysis will be completed centrally once all patients have completed 12 months follow up.
Primary outcome measures will be primarily descriptive and will include proportion of participants:
- whose lesions regress to CIN1 or less at both follow up visits (i.e., at 6 months and 12 months) – persistent regression.
- whose lesions regress to CIN1 or less at 12 months – single regression.
- whose lesions remain high grade at 12 months (i.e., CIN2 or CIN3).
- who progress to microinvasive or invasive cancer.
- who require treatment (and reason for treatment).
- who are lost to follow up (greater than 9 months).

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Participant recruitment difficulties
Safety concerns
Date of first participant enrolment
Anticipated
3/09/2018
Actual
18/10/2018
Date of last participant enrolment
Anticipated
31/12/2019
Actual
27/06/2019
Date of last data collection
Anticipated
27/06/2020
Actual
Sample size
Target
50
Accrual to date
Final
9
Recruitment outside Australia
Country [1] 8946 0
New Zealand
State/province [1] 8946 0
Waikato, Canterbury

Funding & Sponsors
Funding source category [1] 296632 0
University
Name [1] 296632 0
University of Otago - Christchurch
Country [1] 296632 0
New Zealand
Funding source category [2] 296634 0
Hospital
Name [2] 296634 0
Canterbury District Health Board
Country [2] 296634 0
New Zealand
Funding source category [3] 300431 0
Government body
Name [3] 300431 0
Lottery Health Research
Country [3] 300431 0
New Zealand
Primary sponsor type
University
Name
University of Otago, Christchurch
Address
Private Bag 4711
Christchurch 8140
Country
New Zealand
Secondary sponsor category [1] 295594 0
Hospital
Name [1] 295594 0
Canterbury District Health Board
Address [1] 295594 0
Private Bag 4710
Christchurch 8140
Country [1] 295594 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297864 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 297864 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington 6140
Ethics committee country [1] 297864 0
New Zealand
Date submitted for ethics approval [1] 297864 0
13/04/2018
Approval date [1] 297864 0
05/07/2018
Ethics approval number [1] 297864 0
16/STH/201/AM03

Summary
Brief summary
In 2018, the NZ cervical screening age will increase from 20 to 25 years. This will lead to a delay in the diagnosis and treatment of high grade cervical abnormalities in young women of up to 5 years. Cervical cancer is rare in young women and cervical screening in women aged 20-24 has been shown to have little to no impact on rates of invasive cervical cancer up to age 30. Despite this, currently, ~1100 NZ women aged 20-24 years are diagnosed with high grade cervical cell abnormalities (CIN2 and 3) each year. Usually these women are treated and we have a poor understanding of the impact of deferred diagnosis on these lesions. However, there is growing evidence that a high proportion of CIN2 lesions naturally resolve in young women. In contrast, data regarding CIN3 regression rates are lacking and the impact of delayed CIN3 diagnosis and treatment in young women is poorly understood.
The primary aims of the pilot study are to document over 12 months, for a cohort of n=50 women under the age of 25 with a diagnosis of CIN3; safety of delayed identification and treatment of CIN3 in young women, recruitment rate, and to give an indication of CIN3 regression rates. Women <25 years with biopsy-diagnosed CIN3 (including CIN2/3) will be identified in large colposcopy centres in NZ and invited to participate. Pathology and cytology specimens will be reviewed at a multidisciplinary meeting. Provided they meet eligibility criteria, consenting women will undergo observational management (i.e., repeat colposcopy, cytology, and cervical biopsy performed every 6 months for up to 12 months). Treatment is indicated if the patient becomes symptomatic, there is suspicion of invasive or glandular disease, the patient requests treatment, the patient completes 12 months follow-up or at their first follow-up after their 25th birthday (whichever is sooner) without demonstrating persistent regression. Regression is defined as two consecutive colposcopy follow-ups showing CIN1 or less. The trial will be terminated prematurely if; invasive carcinoma of the cervix (>1a) is diagnosed in any study participant; or microinvasive squamous carcinomas are diagnosed >2% of study participants. Primary outcome measures: Proportion of participants 1) whose lesions regress to CIN1 or less, 2) who progress to invasion, 3) who require treatment, and 4) who are lost to follow up. We hypothesise that CIN3 observational management can be safely performed for women aged less than 25 years and that within this hypothesis, we estimate that no women will develop >1a carcinoma, <5% of participants will be lost to follow up and the recruitment rate will be at least 40% of eligible participants.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75306 0
A/Prof Peter Sykes
Address 75306 0
Department of Obstetrics & Gynaecology
University of Otago, Christchurch
Christchurch Women's Hospital
Private Bag 4711
Christchurch 8140
Country 75306 0
New Zealand
Phone 75306 0
+64 3 364 4647
Fax 75306 0
Email 75306 0
[email protected]
Contact person for public queries
Name 75307 0
Peter Sykes
Address 75307 0
University of Otago, Christchurch
Christchurch Women's Hospital
Private Bag 4711
Christchurch 8140
Country 75307 0
New Zealand
Phone 75307 0
+64 3 364 4647
Fax 75307 0
Email 75307 0
[email protected]
Contact person for scientific queries
Name 75308 0
Peter Sykes
Address 75308 0
University of Otago, Christchurch
Christchurch Women's Hospital
Private Bag 4711
Christchurch 8140
Country 75308 0
New Zealand
Phone 75308 0
+64 3 364 4647
Fax 75308 0
Email 75308 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
IPD not planned


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
3214Informed consent form  [email protected]
3215Study protocol  [email protected]



Results publications and other study-related documents

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