Truscreen cervical screening system

Truscreen cervical screening system

Author: Catherine Stringer

Checked: Stewart Montano

KEYWORDS: Clinical trial, Accuracy, Evaluation, and General Screening Project

Abstract:

DOCUMENT HISTORY

Table of Contents

Page

1. Selection CRITERIA

The TruScreen is designed as a primary cervical screening device, and therefore the entry criteria for this trial specify a broad cross-section of woman in the general screening population. Clinicians are requested to include women to whom they would normally perform general cervical screening. Once the site has started the trial all women to whom general cervical screening is indicated should be included, until the site has completed the target number. The site will perform the assessment, diagnosis and management of the women according to best local clinical practice for management of their patient.

1. inclusion criteria

The patient must meet the following criteria to enter the trial:

1. Able to understand the conditions of the trial.

2. Willing and able to sign the patient information sheet and consent form.

2. exclusion criteria.

The clinician is asked to confirm that the woman does not have any of the following exclusion criteria:

1. Under the age of 18 and over the age of 65 years,

2. Recent (<6 weeks) Pap smear;

3. Current menstrual period with heavy flow (days 1-3);

4. Known to be pregnant or less than 4 months post-delivery;

5. Received surgical treatment to the cervix in previous 3 months (including punch biopsies);

6. Previous hysterectomy (corpus and cervix);

7. Receiving experimental photodynamic therapy or otherwise exposed to photosensitive drugs, or suffering from a photosensitising disease (eg, porphyria, lupus erythematous);

8. Has received radiotherapy treatment in the pelvic region at any time previously;

9. Receiving chemotherapy, or has received chemotherapy within the last 5 weeks.

10. In the past three months and currently participating in any other clinical trial or trials other than epidemiology studies.

2. Treatment of Patients

Women will generally be attending for a general routine gynaecological screening and/or pelvic examination. The patient will be given the patient information sheet and the consent form. If they agree to participate in the trial, the informed consent process will be performed by the clinician according to GCP guidelines. The patient will be given a copy of the patient information sheet and consent form to take home with them. Patients will then receive a TruScreen examination immediately after vaginal speculum insertion, then +/- Pap smear, ThinPrep, HPV DNA sampling, VIA, colposcopy and biopsy, pelvic examination and appropriate investigations according to best local clinical practice (Figure 1).

All tests and examinations (cytology and histology) may be performed according to routine procedures and best local clinical practice. Practices with a colposcope available (or ready access to referral colposcopy) may be preferred for the trial. If a patient undergoes a colposcopy examination, biopsy should be performed as clinically indicated (with image capture if available) and in accordance with the routine optimal management of the patient. The clinical procedures for participating general screening institutions are summarised in Figure 1.

The patient management procedures may follow the following sequence:

• Description of the trial and invitation to participate.

• Inclusion/exclusion checklist.

• Explanation and collection of the patient's written informed consent. Documentation of the consent process in the patients’ clinical records or hospital notes.

• Medical history and review of coexistent diseases and concomitant medications.

• TruScreen examination.

• Pap smear, ThinPrep, and/or HPV DNA sampling (according to best practice).

• Colposcopy and acetic acid/iodine staining.

• Image capture pre biopsy (if available)

• Colposcopically directed punch biopsy, if clinically indicated. Document procedure.

• Record colposcopic impression.

• Image capture post biopsy (if available).

• Record any adverse events or complications.

1. TRUSCREEN EXAMINATION

The TruScreen examination will be generally performed using the documented spot probing technique (Attachment E).

1. Excessive discharge or mucus may be removed prior to the commencement of probing. However, the technique used should ensure that the tissue of the cervix is not traumatised. Suitable techniques may include dry swabbing with gauze or cotton, removal of mucus with ring forceps, or a gentle saline wash.

2. The cervix should be probed in two areas - the posterior and the anterior.

3. A "spotting" technique should be used. The handpiece should be placed on a spot on the surface of the cervix at an appropriate angle and with sufficient pressure so that good tissue contact is achieved. The handpiece should be held in place for approximately 2 seconds (30-40 observations). The prompts given on the handpiece monitor should be used by the operator as a guide to moving the handpiece to the next spot.

4. The probing method (attachment E) should be performed with the operator progressing from one side of the cervix to the other, and moving by one probe diameter from one spot to the next. This method should be repeated until the first half of the cervix is tested, then be repeated on the remaining half of the cervix.

5. It is important that spot measurements are not overlapped.

6. It is important that the entire cervix is covered not just areas that look abnormal to the naked eye

If the TruScreen result is “abnormal” ie pNorm <0.5 – (attachment D) the patient will have a Colposcopy examination following the collection of the cytology sample. If clinically indicated a biopsy may be taken at that time.

If the TruScreen result is “normal” ie pNorm >0.5, the participating site will follow normal clinical practice and wait for the cytology result.

• Following the receipt of the cytology result, if the result is ASCUS (Atypical Squamous Cells of Undetermined Significance) or above, the patient will need to be recalled and the patient will have a Colposcopy examination. If clinically indicated a biopsy will be taken at that time also. Any additional testing normally done in this situation by the participating institution should continue to be followed.

• If the cytology result is “normal” – normal clinical procedure should be followed – this likely to be no further treatment.

The clinician performing the TruScreen examination will write the ID code on the Master Subject Log. In addition, the clinician will peel off the unique SUS serial number stickers from the SUS packet (Appendix D) and affix label B to the CRF in the allocated space and label C to the TruScreen print out. The TruScreen print out becomes source data.

Once all information and reports have been collated each CRF will be checked for completeness, signed by the clinician and returned to the Sponsor. The CRF may be emailed or faxed back, as arranged with each site.

If according to local best practice, the following tests (including and not limited to) may be performed:

PAP SMEAR

A Pap smear may be collected following the TruScreen examination. A conventional and/or ThinPrep (liquid cytology) Pap Smear/s may be obtained. Cytological sampling will follow standard hospital clinical procedures. The results of the Pap smear may be recorded on the CRF pages.

HPV DNA TESTING

HPV DNA testing may be performed following the TruScreen examination. The sites are to follow standard hospital clinical procedures; the HPV DNA test may be performed in conjunction with the ThinPrep test.

The use of HPV DNA testing for patients with an abnormal Pap smear diagnosis may provide clinicians with added information as to the individual patient's risk of developing invasive disease. This result can also aid in the determination of follow-up protocols. Written information and a verbal discussion regarding the HPV testing will be provided to each patient before informed consent is obtained. The significance of the result to clinical management will be at the decision of the clinician. The HPV DNA test result may be recorded on the CRF.

2. COLPOSCOPIC PROCEDURE

At the end of the probing session and after the Pap Smear has been performed (if required), a colposcopy may be performed (at this visit) or depending on the results the patient may attend for a follow up visit. For sites where image capture is available, an image of the cervix may be taken prior to a biopsy.

3. BIOPSY PROCEDURE

The clinician will determine how many biopsies are appropriate. In most cases in which an abnormality is observed colposcopically, multiple punch biopsies may be appropriate. In cases where biopsies have been taken from suspected abnormal areas, the biopsy findings may be used to confirm the colposcopic assessment for comparison of the TruScreen results.

If separate analysis is to be done for each biopsy, each sample will be clearly numbered and the location of each numbered biopsy site will be entered onto the CRF. Each biopsy may be reported separately by the histologist and recorded in the relevant fields of the CRF. This will allow direct correlation between the histology and colposcopy results. Following a biopsy of the cervix, the clinician is asked to stop the bleeding by holding a swab on the biopsy site for 10 seconds. Then take a post biopsy image before the bleeding starts again. The images should be made available to the sponsor/third party independent review upon request. Multiple biopsies should be encouraged.¹

Several separate analyses of the histopathology samples may be performed. This may vary between sites depending on the individual requirements of each. The histopathologist at the local laboratory will receive the clinical information recorded on the accompanying pathology request form (however, the histopathologist will not be provided with the results of the TruScreen examination).

Following analysis at the local laboratory, the slide/s may be transferred to an independent laboratory and identified with an indexing number only. The independent histopathologist may not be given any clinical information about the patient. In each case, the overall patient histology result for each patient will be considered to be the highest-grade diagnosis from any of the biopsies taken from the same patient.

Clinicians will be asked to complete and return to Truscreen the CRF for each patient, with the results of the investigations performed including and not limited to TruScreen, Pap smear, Colposcopy and histology (Attachment A). The CRF may be emailed or faxed back, as arranged with each participating site.

3. Assessment of Efficacy

Examination of all the enrolled women will follow standard clinical protocol for a pelvic examination, with the inclusion of a TruScreen examination immediately after vaginal speculum insertion and prior to colposcopic assessment. The TruScreen examination will add 1 – 2 minutes to the total procedure time. The suggested technique is described in the TruScreen Cervical Cancer Screening manual.

The image (attachment D) shows the location of the pNorm value on the verbose report printed following completion of the TruScreen examination. This result may be a number between 0 and 1 (4 significant figures) or a 3-letter code if encryption is being used (see Attachment F – Site specific details). If encrypted, the letters are case sensitive and must be transcribed or entered on data forms exactly as it is printed on the report. This result will be recorded on the CRF and will be analysed for reporting in the final study report.

4. Assessment of Safety

Cytology and histology will be carried out according to established procedures at the sites. The Bethesda system of classification will be used for the reporting of cytology results on the CRF (Attachment A). Once a patient undergoes a TruScreen and colposcopy examination, a biopsy should be performed as clinically indicated and in accordance with the routine optimal management of the patient.

The sites will send the completed CRFs to the sponsor within 7 days of the patient's visit. The Cytology and histology results should also be sent to the sponsor and within 7 days as agreed in the Memorandum of Understanding. The sponsor will provide updates on a regular basis to the TruScreen Medical Advisory Committee.

The CRFs are to remain on site until all the data queries have been resolved and the database is locked. Archiving can be completed when the final study report has been released.

1. ADVERSE EVENTS

All complications or adverse event (AE) will be recorded and documented in the patient's clinic or hospital notes and then recorded on the CRF, whether or not they are related to the use of the TruScreen. The patient's clinic or hospital notes will include the event name/diagnosis, start and stop date, the medical intervention prescribed, and relationship to investigational device. AE reporting will follow the normal post-marketing surveillance channels as customary in the country involved according to the Memorandum of Understanding.

2. SERIOUS ADVERSE EVENT

A Serious Adverse Event (SAE) is:

Any untoward medical occurrence that:

• Results in death,

• Is life-threatening, (NOTE: The term "life-threatening" in the definition of "serious" refers to an event/reaction in which the patient was at risk of death at the time of the event/reaction; it does not refer to an event/reaction which hypothetically might have caused death if it were more severe)

• Requires in patient hospitalisation or prolongation of existing hospitalisation,

• Results in persistent or significant disability/incapacity,

• Is a congenital anomaly/birth defect, or;

• Is a medically important event or reaction.

Medical and scientific judgment should be exercised in deciding whether other situations should be considered serious, such as important medical events that might not be immediately life-threatening or result in death or hospitalisation but might jeopardise the patient or might require intervention to prevent one of the other outcomes listed in the definition above. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation.

The follow up of the SAE will be according to Australian Medical Devices Guidelines http://www.tga.gov.au/docs/pdf/devguid1.pdf (a copy is located in the Investigator DF). In the case of any serious adverse effects (SAE) or complications reported by patients or noted by the attending clinician attributable to the use of the TruScreen, or in the unlikely event that a patient dies, the event must be reported to the Clinical Implementation Team within 48 hours, and reported to the HREC if applicable.

5. Statistics

All patients will have a TruScreen examination followed by +/- Pap smear, ThinPrep, HPV DNA sampling, VIA, colposcopy and biopsy, pelvic examination and appropriate investigations.

The analysis will include sensitivity calculation of the TruScreen, which may be compared to abnormal Pap smear. Each patient will have the pNorm recorded from the TruScreen examination – this is made possible through the use of the verbose report and/or encryption.

The TruScreen Medical Advisory Committee can ask for the trial to be put on hold or terminated for safety reasons. Truscreen as the sponsor has the right to terminate the study at any time. Notice of termination and an explanation will be provided in writing to the Principal Clinician and the HREC, or equivalent at participating sites.

6. Direct Access to Source Data/Documents

The sponsor will be responsible for monitoring the trial and maintaining contact with the site during the course of the trial to monitor progress, review the clinical data, and help with any queries or problems.

The investigator will permit the sponsor and/or agent from the relevant regulatory authority or appointed member from the HREC, or equivalent, if requested, to inspect all case record forms and corresponding portions of the study patients' original office and/or hospital records.

The Clinical Implementation Team responsible for the on-site surveillance may check the CRF pages for accuracy and completeness and corresponding portions of the study patients' original office and/or hospital records. All CRF pages will be collected and accounted for in the analysis of the trial. The site will assist in ongoing data analysis by sending a copy of the full verbose report to the sponsor.

7. Quality Control and Quality Assurance

This trial has been reviewed and approved by the Quality Assurance Officer and the TruScreen Medical Advisory Committee at Truscreen.

8. Ethics

HREC approval for the trial should be obtained as required at each site. It is the responsibility of Participating Project Partner in the Memorandum of Understanding to obtain HREC approval, if required. The advice of the principal clinician will be sought in each case even if the HREC does not feel entitled to deal with the trial; documentation of this decision is needed.

The following documents are filed in the investigator DF. The trial will be conducted in accordance with the guidelines as set down in the:

• ‘Declaration of Helsinki’ (http://www.fda.gov/oc/health/helsinki89.html.)

• National statement on Ethical conduct in Research involving Humans (http://www.nhmrc.gov.au/publications/synopses/_files/e35.doc)

• Note for Guidance on Good Clinical Practice (http://www.tga.gov.au/docs/pdf/euguide/ich/ich13595.pdf)

The patient information sheet and consent form must be printed on the participating site letterhead. Each page of this document should be numbered and the original signed and dated document be filed in the Investigator DF supplied at the beginning of the trial by Truscreen. A sample patient information sheet and consent form is available in Attachment B.

Women will be recruited within the gynaecology outpatient’s clinic. TruScreen technology and the familiarisation trial will be explained by the clinician to the potential participant. The potential patient will be given the patient information sheet and consent form to read. If the woman agrees to participate, she will be asked to sign and date the patient information sheet and consent form, the original will be filed in the Investigator DF and a copy will be given to the patient to keep. Patient confidentiality will be preserved, all personal data will be de-identified and no patient names will be included on the CRF.

9. Data Handling and Record Keeping

For each patient the following data will be accessed from the source documents for recording onto the CRF.

• Demographic data – Patient ID, age.

• Assessment of signs and symptoms at visit.

• Any concurrent therapy given.

• +/- Pap Results (Bethesda classification).

• TruScreen data including serial number of SUS used (SUS label B), pNorm value and number of spots collected.

• Colposcopy findings +/- biopsy results.

• Adverse Events, outcome and resolution.

Once all information and reports have been included, each CRF will be checked for completeness, signed by the clinician and returned to the Sponsor.

The sponsor may send data queries to the site. The site should answer the query within 7 working days. The site will fax the resolved data query to the sponsor, then file the original signed data query in the patients CRF. The resolved data query becomes a CRF page. The resolved data queries together with the original CRF will be collected/sent to the sponsor at archiving.

All patient files and other trial records will be retained by the investigating institution and the sponsor for a minimum period of fifteen years.

10. Financing and Insurance

The participating site will not charge the patients for the TruScreen screening. The cost of the test will include the use of the TruScreen Single Use Sheath (SUS). The SUS is a high-technology sheath provided for one time use to protect against patient cross-infection.

Participating sites in the Trial described in this document will be offered the SUS and supplied equipment free of charge by agreement between the local Distributor and Truscreen Ltd. The agreement includes with the return of the completed CRF, as contracted in the Memorandum of Understanding for each site. Operator training and customer support will be agreed by the local distributor and Truscreen prior to trial start up.

11. Publication

Within three months of the last patient out of the trial, the Trial Chairman will make available a draft of the trial analysis. Within four months of the last patient out, the Trial Chairman or appointed representative will present the final trial report to the Truscreen TruScreen Medical Advisory Committee. The report would also include all reported SAEs as laid down in the SAE forms.

Since the trial may provide information on the use of the product in day-to-day medical practice in a large population of patients, publication of the results will be of interest to other members of the medical profession as agreed in the Memorandum of Understanding.

Patient results in the trial may be reported/disclosed (in a manner that will not identify individual patients) to Truscreen’ authorised personnel, regulatory agencies worldwide and in medical literature and scientific papers.

Figure 1. - Clinical Procedure

1

ATTACHMENTS

ATTACHMENT A- CASE REPORT FORM

Case Report Form

The evaluation of Truscreen in Cervical Cancer Screening.”

“General Screening Project”

(Please complete in blue or black pen)

PART 2: PATIENT HISTORY

PART 4: COLPOSCOPIC EXAMINATION

PART 5:BIOPSY EXAMINATION RESULTS.

PART 6 ADVERSE EVENTS

PATIENT INFORMATION SHEET

The evaluation of Truscreen in Cervical Cancer Screening IN THE GENERAL SCREENING POPULATION

You have been asked to participate in this trial because we consider that you can help us in our research to investigate TruScreen, a new device developed to screen pre-cancerous and cancerous changes on the cervix (neck of the womb). It is anticipated that the TruScreen screening may add one to two minutes of time to the normal gynaecology visit. TruScreen has marketing approval in Europe and Australia.

TruScreen is composed of a ‘probe-like’ handpiece with disposable single use sensor connected to a small processing and interpretation unit. The handpiece, which comes into contact with the cervix, uses very low levels of light and electricity to determine if the cells on the cervix are normal or abnormal. The sponsor pays for the costs of your participation in the TruScreen examination.

If you agree to participate in this trial, the examination will be carried out as follows. The doctor who is carrying out the research will insert a speculum. A TruScreen handpiece with a disposable tip will then be guided into your vagina and carefully moved over the surface of your cervix to ensure the whole cervix is screened. This procedure takes 1 - 2 minutes and you should have no discomfort from this. The TruScreen screening has been tested on more than 10,000 women and no significant effects have been reported with the use of this instrument. There has been some minor abrasion and bleeding in a few cases.

The TruScreen test plays no role in your diagnosis or treatment and you may not be given the results of the test. Depending on the results of your routine examinations such as Pap smear you may be recalled to the clinic for further investigations such as a colposcopy according to established hospital guidelines.

As part of your routine examination, images of your cervix may be captured digitally and kept on record. These images will not identify you in any way and may be made available to the sponsor upon request. If your doctor recommends a biopsy of the cervix, you may feel some discomfort when the biopsy is being taken and some pain – similar to period pain. There may be some spotting following the biopsy.

While we intend that this research trial furthers medical knowledge and may improve detection of cervical abnormalities in the future, it may not be of direct benefit to you. It is also a future prospect of the TruScreen to possibly improve cervical screening practices in developing countries, where the Pap smear is not readily available.

Your data will be confidential and anonymous, and you will not be identified in any presentation or publication that results from this trial. Your clinical data and results will be held in a secure storage facility for at least fifteen years.

Participation in this trial is entirely voluntary, you are in no way obliged to participate – if you do participate – you can withdraw at any time. Whatever your decision, please be assured that it will not affect your medical treatment or your relationship with the medical staff. Only your doctor will be aware of your participation or non-participation.

When you have read this information sheet, your doctor will discuss this with you further and answer any questions you may have. This information sheet is for you to keep.

If you feel you have suffered by participating in this TruScreen trial, please contact Dr ____________ on telephone number __________.

CONSENT FORM

The evaluation of Truscreen in Cervical Cancer Screening IN THE GENERAL SCREENING POPULATION

1. I_______________________________________________________________agree to participate as Patient in the trial described in the Patient Information Sheet.

2. I acknowledge that I have read and understood the Patient Information Sheet, which explains why I have been selected, the aims of the trial and the nature and the possible risk of the investigation. The statement has been explained to me to my satisfaction.

3. Before signing this Consent Form, I have been given the opportunity to ask any questions relating to any possible physical and mental harm I might suffer as a result of my participation. I have received satisfactory answers to my questions that I have asked.

4. I understand that my decision whether or not to participate will not prejudice my present or future treatment, or my relationship with the hospital, or any institution co-operating in this trial, or any person treating me. If I decide to participate, I am free to withdraw my consent and to discontinue my participation at any time without prejudice.

5. I agree that research data gathered from the results of the trial may be published, provided that I cannot be identified.

6. I understand that if I have any questions relating to my participation in this research, I may contact the trial doctor, Dr ____________ on telephone number __________, who will be happy to answer my questions.

7. I acknowledge receipt of a copy of this Consent Form and the Patient Information Sheet.

Patients Signature _______________________ Date________________________

Please PRINT name _______________________

Investigators Signature_______________________ Date________________________

A

See over page for pNorn location

ATTACHMENT C – TRUSCREEN PRINT OUT

Location of pNorm.

Alternatively, the result may be encrypted to a case sensitive 3 letter code

A

Peal and stick onto TruScreen print out

TTACHMENT D - SUS PACKAGE LABELLING (EXAMPLE)

Peal and stick onto CRF page

ATTACHMENT E - PROBING PATTERN

During TruScreen® examination, the following coverage patterns on the cervix, as shown below, is recommended:

• Follow the above pattern to probe the cervix, starting from the 9 o'clock position, on the outer area ectocervix. Ensure full coverage of the anterior part of ectocervix.

• Follow the pattern below to probe the posterior part of ectocervix.

Precautions

• Do not overlap the spots too much

• Probe to cover the entire cervix

• Do not over-probe any ectropion (erosion) area

ATTACHMENT F - SITE SPECIFIC DETAILS

1.1 SCHEDULE

MAR/2015: Site selection.

APR/2015: Signing of Memorandum of Understanding

APR/2015: Registration of participating centres

MAY/2015: TruScreen Training

JUN/2015: Project Commences

NOV/2015: Project Completion

DEC/2015: Data analysis and final report.

1.3 Authorised protocol signatories.

The Project Chairman authorised to sign the protocol and amendments is:

1.4 Medical Adviser

The Medical Adviser for this project is:

1.7 Site/s

It is anticipated that the project will involve a total of xxx patients the site as documented below.

The participating site will be as follows:

7. Assessment of Efficacy

The console provided will give a VERBOSE report.

9. STATISTICS

Recruitment is anticipated at approximately XX patients per month from each site. This sample size is expected to yield histologically acceptable for a primary outcome.

The analysis will include sensitivity calculation of the TruScreen compared to abnormal Pap smear. The primary endpoint is the colposcopy and biopsy outcome. Each patient will have the pNorm recorded from the TruScreen examination – this is made possible through the use of the verbose report.

DMU Timestamp: February 19, 2015 14:07