truscreen cervical screening system

Truscreen Pty Limited.

Ref.no: К0000110-01

Truscreen cervical screening system

Author: Catherine StringerChecked: Stewart Montano

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

Abstract:

DOCUMENT HISTORY

Rev No.:Change Note:Date Prepared:Date Released:

Rev No.:Change Note:Date Prepared:Date Released:

General Screening Project K000110 – 01 of 39

General Screening Project

Table of ContentsPage

1. General Information 4

1.1 Schedule 4

1.2 Sponsor and Monitor 4

1.3 Authorised Protocol Signatories 4

1.4 Medical Adviser 4

1.5 Abbreviations 4

1.6 Definitions 5

1.7 Participating Sites 10

1.8 Clinical Laboratories 10

2 Background Information 10

2.1 Technical description the device 10

2.2 Risk benefit analysis 11

2.3 Benefits/justifications 12

2.4 Compliance with the protocol 12

2.5 Population to be studied. 12

2.6 Supporting Documents 13

3 Trial Objectives and Purpose 13

4 Trial Design 14

4.1 Description of the Trial 14

4.2 Patient Withdrawal 14

4.3 Accountability Procedures 144.3.1 SUS Units 144.3.2 Patient ID 15

4.4 Source Data. 15

5. Selection Criteria 16

5.1 Inclusion criteria 16

5.2 Exclusion criteria 16



6 Treatment of Patients 17

6.1 TruScreen Examination 17

6.2 Colposcopic procedure 18

6.3 Biopsy Procedure 19

7 Assessment of Efficacy 19

8 Assessment of safety 20

8.1 Adverse Events.20

8.2 Serious Adverse Events20

9 Statistics 21

10 Direct access to source data/documents21

11 Quality control and quality assurance 21

12 Ethics 21

13 Data handling and record keeping 22

14 Financing and insurance 23

15 Publication policy23

16 Attachments 24

ATTACHMENT A - CASE REPORT FORM 25

ATTACHMENT B - PATIENT INFORMATION SHEET AND CONSENT FORM 33

ATTACHMENT C - TRUSCREEN PRINT OUT 35

ATTACHMENT D - SUS PACKAGE LABELLING (EXAMPLE) 36

ATTACHMENT E - PROBING PATTERN 37

ATTACHMENT F - SITE SPECIFIC DETAILS 39


General Screeningl Project

1. GENERAL INFORMATION

Truscreen Clinical Implementation Team will be responsible for the overall coordination of the General Screening Project (General Screening Population Project).

1.1 SCHEDULE

See ATTACHMENT F - SITE SPECIFIC DETAILS

1.2 SPONSOR AND MONITOR:

The sponsor and monitor of this trial is:

1.3 AUTHORISED PROTOCOL SIGNATORIES.

The Trial Chairman authorised to sign the protocol and amendments is:See ATTACHMENT F - SITE SPECIFIC DETAILS

1.4 MEDICAL ADVISER

The Medical Adviser for this trial is: See ATTACHMENT F - SITE SPECIFIC DETAILS

1.5 ABBREVIATIONS

AE Adverse EventADE Adverse Device Event AIS Adenocarcinoma in Situ ARTG Australian Register of Therapeutic Goods ASCUS Atypical Squamous Cells of Undetermined SignificanceAWE Aceto White Epithelium CIS Carcinoma in SituCIN Cervical Intraepithelial Neoplasia CRF Case Report FormGCP Good Clinical PracticeDF Documentation Folder DNA Deoxyribonucleic acid HGEA High Grade Epithelial Abnormality HSIL High-Grade Squamous Intraepithelial Lesion HREC Human Research Ethics CommitteeHRT Hormone Replacement Therapy HPV Human PapillomavirusID Identification LSIL Low-grade squamous intraepithelial NCI National Cancer InstituteOSE Original squamous epithelium PCR Polymerise chain reaction DF Documentation Folder


General Screening ProjectpNorm Probability of normalpmol/L picomol per Litrepg/mL picograms per millilitrePRN When requiredRCI Reid Colposcopic IndexROC Receiver operator characteristic SAE Serious Adverse EventSTD Sexually Transmitted Disease SIL Squamous Intraepithelial lesion SCJ Squamocolumnar JunctionSUS Single Use Sensor TGA Therapeutic Goods Administration TZ Transformation ZoneVIA Visual inspection with acetic acid

1.6 DEFINITIONS

ATYPIAAn abnormality of a cell, which may or may not be associated with later malignancy.

ADENOCARCINOMA OF THE CERVIX A type of cervical cancer originating in the mucus-producing cells of the endocervix.

ADVERSE EVENT Any undesirable clinical occurrence in a Patient whether it is considered to be device related or not, that includes a clinical sign, symptom or condition and/or an observation of an unintended technical performance or performance outcome of the device.

ADVERSE DEVICE EVENT (ADE)A clinical sign, symptom or condition that is causally related to the device implantation procedure, the presence of the device, or the performance of the device system.

ASCUS The acronym in the Bethesda system terminology for atypical/abnormal squamous cells of undetermined significance (ASCUS). It is used for reporting cervical/vaginal cytologic diagnosis describing cellular abnormalities that are more marked than those attributable to reactive changes but that quantitatively or qualitatively fall short of a definitive diagnosis of squamous intraepithelial lesion (LSIL); may reflect a benign or a potentially serious lesion.

BETHESDA SYSTEMMethod of classifying Pap tests developed by the United States National Cancer Institute (NCI) to provide more detailed information about Pap test results.

CARCINOMA IN SITU (CIS) A lesion characterised by cytologic changes of the type associated with invasive carcinoma, but with the pathologic process limited to the lining epithelium and without histologic evidence of extension. The lesion is presumed to be the histologically recognisable precursor of invasive carcinoma.


General Screening ProjectCERVICAL INTRAEPITHELIAL NEOPLASIA (CIN)Dysplastic changes beginning at the squamocolumnar junction in the uterine cervix that may be precursors of squamous cell carcinoma: grade 1, mild dysplasia involving the lower one-third or less of the epithelial thickness; grade 2, moderate dysplasia with one-third to two-thirds involvement; grade 3, severe dysplasia or carcinoma in situ, with two-thirds to full-thickness involvement.

CERVICAL SCREENINGScreening tests that are performed to detect the presence of pre-cancerous or cancerous cervical cells in women who do not present with any symptoms of cervical cancer. Cervical screening tests include TruScreen, Pap tests and direct visual inspection.

CONVENTIONAL PAP (PAPANICOLAOU) SMEAR/TESTThe Conventional Pap Smear test involves the visual examination of fixed, magnified and stained cells and is the currently accepted screening test for cervical cancer and pre-cancer, where ectocervical and endocervical samples are taken. A wooden spatula or a cytobrush are used. A fixation agent is applied to preserve morphological cell structure. The Papanicolaou stain utilises haematoxylin, orange-G-6 and EA preparations.

COLPOSCOPYVisual examination of the cervix using a specially designed instrument, called a colposcope, to view the cervix using magnification to detect abnormal cell changes that may be pre-cancerous (dysplasia or CIN).

CONSENT FORMA document explaining all relevant trial information to assist the trial volunteers in understanding the expectations and requirements of participation in a clinical trial. This document is presented to and signed by the trial subject.

DIRECT VISUAL INSPECTION A cervical screening technique where the cervix is observed directly.

DYSPLASIAAbnormal cell development. Cervical dysplasia is the abnormal growth of cells on the surface of the cervix. These abnormal cells may disappear without treatment (regress) or they may become cancerous.

ECTOCERVIXThe part of the cervix that extends into the vagina. It has a convex surface lined with stratified squamous epithelium.

ENDOCERVIXThe cervical canal. This is lined with columnar epithelial cells.

GOOD CLINICAL PRACTICE (GCP) International ethical and scientific quality standard for designing, conducting, monitoring, recording, auditing, analysing and reporting studies. Insures that the data reported is credible and accurate, and that subject's rights and confidentiality are protected.


General Screening ProjectINFORMED CONSENTInformed consent is a process where the voluntary verification of a patient’s willingness to participate in a clinical trial, along with the documentation thereof is obtained. This verification is requested only after complete, objective information has been given about the trial, including an explanation of the trial's objectives, potential benefits, risks and inconveniences, alternative therapies available, and of the subject's rights and responsibilities in accordance with the current revision of the Declaration of Helsinki.

IMAGE CAPTUREDigital imaging colposcopy allows image capture, processing and objective analysis.

HPV DNA TESTThe HPV DNA Test includes a range of techniques used to test for the presence of numerous high and low risk HPV types in the cervical tissue. These techniques may include PCR and Hybrid Capture.

HPV ATYPIAA type of cellular abnormality typical caused by HPV infection.

TRUSCREENThe TruScreen includes the console, handpiece and Single Use Sensor (SUS) unit.

TRUSCREEN HANDPIECE The TruScreen handpiece is a device, which is intended to be fitted with a new disposable Single Use Sensor (SUS) for each patient to prevent cross-infection. The handpiece with SUS fitted allows the electrical and optical stimulation of cervical tissue. The data collected by the biosensors is compared to an algorithm developed using histologically confirmed tissue signatures.

HUMAN PAPILLOMAVIRUS (HPV)Human Papilloma Virus (HPV) is a common DNA virus. Different types of the virus are associated with warts on the hands, feet and mucous membranes of the oral, anal and genital areas. Over 90 types of HPV have been identified and several are associated with cancerous conditions, including pre-cancerous lesions of the cervix.

METAPLASIASpecifically relating to the cervix, metaplasia is the normal transformation of columnar tissue to squamous tissue.

ONCOGENICCausing, inducing, or being suitable for the formation and development of a neoplasm.

pNORM The probability that the cervical epithelium is normal. The TruScreen uses a level of pNORM=0.5 as a reference level for its reports. Values above this are reported as normal, while levels below were reported as abnormal. This is the level that was used for all of the clinical projects, and the reference used for calculation of sensitivity and specificity. pNORM=0.5 is a suitable level for these determinations, however, the clinician is able to interpret a borderline reading in light of the clinical presentation and patients history.



SENSITIVITYThe ability to detect true-positive matches. In the context of cervical screening it refers to how effective a test is at correctly detecting disease.

SINGLE USE SENSOR (SUS)The Single Use Sensor (SUS) is a sleeve with electrodes and an optical window, designed to be fitted over the TruScreen handpiece and used on a one-time basis only. The SUS is discarded after each patient examination.

SERIOUS ADVERSE EVENT (SAE)See section 8.2

SPECIFICITYThe ability to reject 'false-positive' matches. In the context of cervical screening, it is a measure of how accurate a test is in correctly identifying women who do not have disease

SOURCE DATA All information contained in original records and certified copies of results, observations or other facets required for the reconstruction and evaluation of the trial that is contained in source documents.

SQUAMOUS CELL CARCINOMAThis is the most common type of cervical cancer. It originates in the squamous cells on the surface of the ectocervix.

SQUAMOUS INTRAEPITHELIAL LESION (SIL)Abnormal growth of squamous cells on the surface of the cervix. SILs may be classified as low-grade squamous intraepithelial lesions (LSILs) or high-grade, squamous intraepithelial lesions (HSILs) depending on how abnormal the cells are and how much of the cervix is affected. High-grade, squamous intraepithelial lesions correspond with CIN 2-3.

TRANSFORMATION ZONE (TZ)The area of the cervix where the squamous epithelium of the vagina joins the columnar epithelium lining the cervical canal. In this area, columnar cells are constantly being transformed into flat squamous cells (metaplasia). It is in this transformation zone that abnormal growth or dysplasia is most likely to develop.

VISUAL INSPECTION WITH ACETIC ACID (VIA)A cervical screening technique where a solution of 3-5% acetic acid is applied to the cervix, which is then observed with the naked eye or under magnification.

THINPREP TESTThe ThinPrep Test is a modified Pap Smear test. A sampling device similar to that used for a conventional Pap smear is used to collect a sample. Instead of smearing the cells onto a glass slide, the sampling device is immersed into a cell suspension vial. At the laboratory, an automated slide preparation unit prepares the slide. The result is a slide with a uniform thin-layer of cells, free of obscuring artefacts.



1.7 SITES

Sites will be chosen on the basis of their suitability to undertake the "General Screening Project " in their practices' patient population, the patient throughput numbers, and the interest in the technology on behalf of the clinician. The principal clinician at each site will be responsible for the coordination of their site. The sites participating in this multi-centre trial are listed in ATTACHMENT F - SITE SPECIFIC DETAILS

1.8 CLINICAL LABORATORIES

To enable any procedural differences between sites to be taken into account in the trial analysis the medical adviser will review the local procedures reporting ranges used for cytology and histology prior to the commencement of the trial at each site. The sites involved in the trial will provide the Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/or institutions involved in the review of results.

2. BACKGROUND INFORMATION

2.1 TECHNICAL DESCRIPTION OF THE DEVICE

TruScreen is a novel optoelectronic device, which uses low-level electrical and optical signals to scan the cervix. The response is measured, and computer-based expert system software is then used to classify the tissue response, by comparing the signals with those stored in a computer database representative of the range of cervical tissue types.1,2

If the tissue is abnormal, the TruScreen technology will allow the clinician to immediately make management decisions and communicate these decisions to the patient. Therefore it may minimise the labour intensive follow-up and lessen the chance of a patient being lost to recall.

The TruScreen is composed of a handpiece connected to a compact processing and interpretation console with disposable single use only sensor. The tip of the probe, which is in contact with the cervix, scans the tissue by repetitively pulsing it with low levels of optical and electrical energy. Real-time interpretation of the cervix tissue response is achieved by automatic comparison with a digitally stored catalogue of tissue signatures.

The TruScreen is mains powered with approved patient isolation, delivers several electrical pulses for a duration of approximately one third of a second. Fifteen pulses are delivered per “observation”, and fourteen observations are made per second. These very low energy pulses are below normal sensation thresholds.

The TruScreen optical measurements operate within the visible and near infrared spectrum. The light emitting diodes (LEDs) have a power output range of 7-130 microwatts. The light intensity is far below that of the colposcope. Four LEDs are used to emit light at three discrete wavelengths. The LEDs operate for approximately one hundredth of a second, once per observation, and approximately 14 observations are made per second.

1 Quek SC, Mould T, Canfell K, Singer A, Skladnev V and Coppleson M, The Polarprobe - Emerging technology for cervical cancer screening. Ann Acad Med Singapore 1998: 27; 717-721.2 Coppleson M, Canfell K and Skladnev V, The Polarprobe - An instantaneous optoelectronic approach to cervical screening. CME Journal Gynecol Oncol 2000: 5(1); 31-38.


General Screening ProjectThe handpiece of the TruScreen is a long, thin, pen-shaped instrument approximately 310 mm in length, which is hand-held by the operator. The section of the probe that enters the vagina is less than 150 mm in length with a tip diameter less than 7mm. The tip is used by the operator to scan the cervix during the TruScreen examination.

A disposable sheath or Single Use Sensor (SUS) covers the handpiece, and this sheath is discarded after use. This handpiece is part of the TruScreen device. For diagrams and technical specifications please refer to the TruScreen Cervical Cancer Screening System user training manual and the TruScreen cervical screening system, operators manual.

TruScreen was granted regulatory approval (CE Marking) by the European regulatory authorities in 2014, as a screening instrument for the detection of cervical pre-cancer and cancer.

2.2 RISK BENEFIT ANALYSIS

The risks and benefits of the TruScreen test procedure have been assessed. The investigators participating in this trial will be fully trained in the use and interpretation of the TruScreen system prior to being involved in this trial.

Investigators will be required to fully explain the procedure, potential risk, discomfort and potential benefits prior to witnessing the patient sign informed consent. The safety data associated with the TruScreen System is outlined below:

Testing has been performed to minimise the risk associated with the use of the system. Foreseeable risks associated with the use of the system are cervical abrasion and minor bleeding, and infection. Clinical evaluation of the TruScreen has involved testing of several thousand patients in the UK, Australia, Singapore, The Philippines, Russia, South Korea, China and Brazil. No major patient complications were noted in this population. The following effects were noted in a small number of patients: minor abrasion and bleeding, patient anxiety and discomfort (consistent with the level associated with the Pap Smear test).

A survey of 152 women was conducted to examine their reaction to being tested with the Pap smear and with the TruScreen.3 The TruScreen was associated with less anxiety and fewer after effects such as bleeding and discomfort. Of the tested population, 82% preferred the TruScreen to the Pap Smear, 16% did not care, and 2% preferred the Pap smear.

Within this trial, all patients will receive TruScreen followed by +/- Pap smear, ThinPrep, HPV DNA sampling, VIA, colposcopy and biopsy, pelvic examination and appropriate investigations according to best local clinical practice. Patient care will not be based solely on the results of the TruScreen test performed in the trial as in Figure 1.

The risks associated with the TruScreen Single Use Sensor (SUS), have also been discussed and addressed. These are covered in the technical report ‘Risk Analysis – Cervix Digital System – Frontview and Single Use Sensor (SUS). Truscreen Document P00000724’. Use of the SUS introduces no additional risks than those associated with the TruScreen, discussed previously.

3 Mould TAJ, Quek SC, Lovegrove J, Gallivan S, Singer A, The acceptability of cytological screening for cervical cancer compared to a new electronic screening device - the Cervix Digital System. Proceedings of the EUROGIN Third International Congress, March 1997.



In view of the above factors, patient risk is considered to be of a low level when compared to routine colposcopic examinations.

2.3 BENEFITS/JUSTIFICATIONS

The major potential benefits resulting from the use of the TruScreen include its use as a primary screening tool, as an adjunct to the Pap Smear, incorporated as part of the screening triage, as an adjunct to HPV testing, incorporated as part of the screening triage.

The TruScreen can provide patients with an instantaneous result eliminating the waiting time and consequent patient anxiety associated with the current Pap smear screening system.

TruScreen can also improve cervical screening practices in developing countries, where Pap smear is not readily available. The benefits of using the TruScreen includes reduced cost, no need for supporting infrastructure and most importantly an instantaneous result that will enable patient management and treatment options to be discussed and possibly completed within the same visit.

The Single Use Sensor (SUS) provides the convenience of a disposable sleeve, eliminating any risk of cross contamination between patients. One SUS is used per patient.

2.4 COMPLIANCE WITH THE PROTOCOL

The sites undertake that the trial will be conducted in compliance with the protocol, GCP and applicable local and international regulatory requirement(s) as outlined in their Memorandum of Understanding. If the site does not comply with the protocol or signed agreements, Truscreen reserves the right to terminate the agreement with the Principal Clinician and/site.

Appropriately trained Truscreen personnel may perform the trial monitoring, e.g., Clinical Implementation Team particularly during the first stages of the trial and during the trial. They will check for the accuracy and completeness of data collected during the trial.

2.5 DESCRIPTION OF THE POPULATION TO BE STUDIED

The women studied will be over the age of 18 and under the age of 65 who meet all of the inclusion and none of the exclusion criteria who attend the clinic for general routine cervical screening.



2.6 SUPPORTING DOCUMENTS

Canfell K, Clinical Investigation Plan: Cervix Digital System Performance Evaluation and Development Studies. Truscreen Document K0000044.

Canfell K, Evans J, Nassar N, Clinical Protocol: Frontview Reusable Cervix Digital System Evaluation and Development Study. Truscreen Document K0000001.

Coppleson M, Reid BL, Skladnev VN and Dalrymple JC, An Electronic Approach to the Detection of Pre-Cancer and Cancer of the Uterine Cervix: A Preliminary Evaluation of Polarprobe. Int J Gynecol Cancer 1994: 4; 79-83.

Jeronimo J, Schiffman M, Colposcopy at the Crossroads. American Journal of Obstetrics and Gynaecology. 2006 Volume 195 Edition 2 pages 349 - 53International Standard IEC 60601-1. Medical Electrical Equipment - General Requirements for Safety.

Mould TAJ, Quek SC, Lovegrove J, Gallivan S, Singer A, The acceptability of cytological screening for cervical cancer compared to a new electronic screening device - the Cervix Digital System. Proceedings of the EUROGIN Third International Congress, March 1997.

Ling B & Heikkinen S, Work Instruction: Cleaning and Handling Procedures for Cervical Handpieces and SUS Units Returned from a Clinical Environment. Truscreen Document K0000049.

Wunderman I, Coppleson M, Skladnev V and Reid BL, Polarprobe: A Precancer Detection Instrument. J Gynaecol Tech 1995: 1; 105-10.

TruScreen cervical screening system Operator's Manual P0001689.

3. TRIAL OBJECTIVES AND PURPOSE

The objectives of the trial are:1. To allow clinicians to gain ‘real world’ experience in the use of the TruScreen system as a general routine screening tool in their health care environment.2. To collect additional information and evaluate the results of the TruScreen system in expanded patient populations.



4. TRIAL DESIGN

4.1 DESCRIPTION OF THE TRIAL

TruScreen will be used to assess women who attend the clinic (listed attachment F section 1.7) for routine general cervical screening. The trial will give clinicians 'real world' experience using the device in the their hospital and healthcare environment. This trial also enables the sponsor to collect additional information to evaluate the results of the TruScreen system in expanded patient population.

Examination of all the enrolled women will follow best local clinical practice for general routine cervical screening. All patients will receive 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. The TruScreen examination may add 1 - 2 minutes to the total procedure time (Figure 1).

The clinical management and treatment of the patient will proceed based on the patients’ general and gynaecological history, presenting signs and symptoms, physical and gynaecological examination, and results of investigations, as the clinician deems appropriate.

4.2 PATIENT WITHDRAWAL

The clinician may terminate a patient’s participation in the trial if he/she determines that it is not in the best interest of the patient or the patient is non-compliant with the trial requirements. Participation is entirely voluntary and a patient can withdraw at any time. This will not affect the patient’s medical treatment or their relationship with practice or the hospital. If a patient chooses to withdraw from the trial, all data collected will be analysed up into the point that the patient withdrew their consent.

4.3 ACCOUNTABILITY PROCEDURES

4.3.1 SUS UNITS

During normal clinical practice, each SUS unit must be discarded immediately after use and disposed of as biohazard waste. Each site is to follow their standard infection control procedures. The materials used in the manufacture of the SUS are pliable, which ensures that sharp edges are not formed as a result of routine handling. Thus, disposal in a 'sharps' container is not required. While it is not intended that the used SUS should be returned to Truscreen for ongoing research and development, if this is becomes necessary, Truscreen will advise how decontamination according to infection control guidelines (Truscreen document K0000049) shall undertake prior to any SUS being returned.

Each SUS unit is packaged in a pouch. The manufacture date is stamped on the pouch and the expiry date is to be checked prior to use (Attachment D). As an additional measure, the body and cord of the handpiece shall be cleaned using a neutral cleaner/hospital grade disinfectant (such as Viraclean) and lint-free cloth at the beginning and end of each clinic session. For correct fitting and removal instructions for the SUS, refer to the TruScreen Cervical Cancer Screening System operator's manual (P0001689).



4.3.2 PATIENT ID

A unique identification (ID) code is allocated for each consented patient at each site. This ID code will be based on the site number (two digit code allocated by Truscreen Clinical Implementation Team) and a three digit sequential number from the Master Subject Log. There will be no duplication of numbers, once a number has been allocated (even if the patient withdraws), this number is not reused. The ID number will always be five digits. The clinician will maintain the Master Subject Log, a list linking the names and addresses of participating women to the patient ID code and the SUS serial number. Truscreen will not collect copies of the Master Subject Log. . The clinician will file the Master Subject Log in the Investigators’ DF which can be reviewed by authorised persons and the Clinical Implementation Team. The clinician will refer to the Master Subject Log, to link the histology and cytology results with the correct patient ID.

If available at the time, the results will be entered in a web based data entry form available to participating sites. This software will be accessible using password protection and will be encrypted for security. No patients’ names will be included, only the ID numbers.

The TruScreen report may be encrypted (see Attachment F for site-specific details). If encrypted the principle investigator will be given the tools to decrypt. In addition, the result can automatically be decrypted in the web-based data entry form or by submission to Truscreen.

4.4 SOURCE DATA.

The source data (paper or electronic) includes and is not limited to the information contained in original records and certified copies of results, observations or other facets required for the reconstruction and evaluation of the trial. There is no direct data capture into the CRF.

Recruitment can commence when “Green Light" has been obtained. Green Light is a document issued from the Clinical Implementation Team at Truscreen to confirm that all the training, documents, equipment and approvals have been obtained from the relevant institutions. Once "Green Light" been obtained all patients whom cervical screening is indicated should be included in the trial until the site has achieved the number as agreed in the Memorandum of Understanding or as negotiated with the Clinical Implementation Team at Truscreen.



5. 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.

5.1 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.

5.2 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.

6. 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.

6.1 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 SMEARA 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 TESTINGHPV 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.

6.2 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.


General Screening Project6.3 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.4

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.

7. 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 Jeronimo J, Schiffman M, Colposcopy at the Crossroads. American Journal of Obstetrics and Gynaecology. 2006 Volume 195 Edition 2 pages 349 - 53


General Screening Project8. 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.

8.1 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.

8.2 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.

9. 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.

10. 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.

11. 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.

12. 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.


General Screening ProjectThe 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.

13. 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.


http://www.fda.gov/oc/health/helsinki89.html

http://www.tga.gov.au/docs/pdf/euguide/ich/ich13595.pdf

http://www.nhmrc.gov.au/publications/synopses/_files/e35.doc


14. 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.

15. 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

Perform TruScreenExamination

TS pNorm <=0.5 “Abnormal”

TS pNorm>0.5 "Normal"

Conduct +/-Pap, ThinPrep and/or HPV

DNA sampling, VIA(if to be performed).

Colposcopy, +/- biopsy as clinically indicated,

Perform pre and post biopsy images (prn),

Record findings.

Wait for cytology results to be

returned

Wait for cytology results

If cytology result is ASCUS or above

If cytology is within normal

limits,

Colposcopy +/- biopsy if clinically indicated Perform pre and post biopsy images (prn),

Record findings.

Complete CRF and send to PLT.Within 7 days


1

4

3

2


ATTACHMENTS

ATTACHMENT A- CASE REPORT FORM

General Screening Project K000110 of 39

Patient IDCase Report Form

The evaluation of Truscreen in Cervical Cancer Screening.”“General Screening Project”

(Please complete in blue or black pen)

Date: / /OFFICE USE ONLY

Date Received: day month year

Patient ID: Date Entered:

Hospital Name:Entered By: Checked

By:

Investigator’s Name:Folder No.: Tape No:

Protocol No: K0000110

PART 1: PATIENT ENTRY CRITERIA Please confirm by ticking ALL boxes:

Pt has been informed of the study, has signed the patient information sheet & consent form. Copy of the information sheet and consent form given to the patient. Aged Between 18 and 65 years of age Has not had a Pap Smear within 6 weeks of this visit. Not currently menstruating with heavy flow (day 1→3) Not known to be pregnant OR less than 4 months post-delivery No previous hysterectomy (corpus and cervix) No surgical treatment to cervix in last three months (including punch biopsies) Not receiving photodynamic therapy; or exposed to photosensitising drugs; or suffering a disease causing photosensitivity.

Not received radiotherapy treatment in the pelvic region at any time previously Not receiving chemotherapy, or has not received chemotherapy within the last 5 weeks In the past three months and currently not participating in any other clinical trial or projects other than epidemiology studies.

PART 2: PATIENT HISTORY

2.1 Date of Birth:/ /

day month year

2.2 Race: Caucasian African Descent Asian – Oriental

Asian – Indian Hispanic

Polynesian

Other (specify)…………

2.3 Post Menopausal: no yes

2.4 Any post-coital bleeding?

no yes


Patient ID2.5 Any Vaginal Discharge

that bothers you? no yes

PART 2: PATIENT HISTORY (cont)

2.6 Presenting Pap Smear

Has Patient ever had a previous abnormal Pap smear (prior to this trial)?

no yes uncertain

If Yes, Specify most recent Pap smear result: (Bethesda)

Result.................................……………… / Month Year

2.7 Tick previous biopsy / treatment to uterus or cervix?

(tick ONE box most recent treatment only) none/unknown punch biopsy loop excision cone biopsy ablation - cryosurgery, electrocautery, laser other……………………………………………

2.8 Which test was used for cytological analysis?:

Conventional Pap Smear ThinPrep Pap Smear Split Sampling (sampling for more than one test)

PART 3: TruScreen EXAMINATION3.1 Is the TRUSCREEN

operator the Clinician? yes no → specify TRUSCREEN Operator Name:

3.2 Mucus/Discharge present prior to probing:

yes not removed with swab with ring forceps

no

3.3 Was there any blood present prior to probing:

none minor bleeding major bleeding

3.4 Details of handpiece used:

Attach label or write down Lot & Serial No of the SUS used

Lot No:……………………………………

Serial No:……………….…………………

Confirm the SUS was discarded following use.


Patient ID

PART 3: TruScreen EXAMINATION (cont)

3.5 Results

pNorm Result_____________________

Encrypted Result__________________

Number of spots

Algorithm Version Number__________

3.6 Were there any complications or observations related to the use of TRUSCREEN?

no complications (tick ALL applicable boxes) minor bleeding major bleeding minor discomfort major discomfort other…………………………………………………………………

PART 4: COLPOSCOPIC EXAMINATION

4.1 Was a colposcopy performed at this session? no → yes →

4.2 Colposcopy Results – Original Colposcopic Impression:

4.2.1 Tissue Type: (tick ALL cervical tissue types seen on cervix )

Normal (absence of CIN)

Low Grade HPV Condyloma CIN 1

High Grade - CIN 2-3

Invasive

Additional Comments

Polyps Nabothian Cysts Inflammation/cervicitis/contact bleeding Atrophy

4.2.2 Transformation Zone:

TZ fully Seen (satisfactory for diagnosis) TZ not fully visible (Unsatisfactory for diagnosis)


Patient ID

4.2.3 Final colposcopy diagnosis:

Normal Low Grade High Grade Cancer Unsatisfactory. Colposcopy examination could not be performed due to

Images captured.

PART 4: COLPOSCOPIC EXAMINATION

4.3 Was a punch biopsy performed? no yes number taken:

4.4 Was any treatment performed?

none loop excision cone biopsy ablation (cryosurgery, electrocautery, laser) hysterectomy

4.5 Comments (related to Colposcopic examination


Patient IDPART 5:BIOPSY EXAMINATION RESULTS.5.1 Centre Name:(centre where Histology performed)

5.2 Histology Reviewer:

5.3 Were clinical notes/patient history supplied with this sample? yes no

Note: Biopsies are labelled numerically as 1,2,3, etc. by the colposcopy clinic.

Ensure that the clinic labels correspond with the slide numbers on this CRF.

Histology Slide/Accession Numbers: O’Clock position (if available)

Biopsy 1:

Biopsy 2:

Biopsy 3:

Biopsy 4:

Histology Results:

Punch Biopsy/s (Numbered)

LEEPCone

Biopsy

Subsequent histology following treatment

Final Patient Histology Diagnosis

(consider all biopsies)

1 2 3 4Date/ /

Unsatisfactory for analysis

Note: Tick ONE box only

Unsatisfactory for Analysis

Acute Cervicitis

Normal

HPV/Atypia

Low Grade

High Grade/

Acute cervicitisNormal squamousNormal columnarImmature metaplasiaMature metaplasiaChronic inflammationOther………………….HPVAtypiaOther…………………CIN ILow grade glandularOther…………………CIN IICIN IIIMicroinvasiveInvasive squamousHigh grade glandularInvasive adenocarcinoma

Other…………………

5.4 Comments (related to Diagnosis)


Patient ID


Patient IDPART 6 ADVERSE EVENTSOnset Date Event Intensity Outcome Stop date Related to IP

Mild Moderate Severe

Recovered Recovered

with sequelae Still Present Died Not known

None Unlikely Possible Probable Definite


Recovered Recovered




Recovered Recovered



Onset date: The date the adverse event began

Event: Description of the event

Intensity:Mild: No interference with functioningModerate: No significant interference with functioningSevere: Significant interference with functioning

Outcome:

Recovered: Patient has made a full recovery.Recovered with sequelae: Patient has recovered but there are some ongoing

problems that will never resolveStill Present: OngoingDied: (SAE report required)Not known: Patient has been lost to follow up and the outcome of the event is

not known

Relationship to IP

None: There is no relationship to the investigational product (IP).Unlikely: The relationship to the IP can not be excluded.Possible: There is a plausible relationship to the IP.Probable: There is reasonable sequence of events related to the IP.Definite: There is no doubt the event is in relation to the IP


Patient ID

PART 7 EQUIPMENT ISSUES AND OTHER OBSERVATIONS:

7.1 Any difficulties with data collection equipment

no

yes describe:

7.2 Other observations or comments:

I confirm that all the above data is correct.

Investigator’s Signature:

Date: / / Day Month Year



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________________________



ATTACHMENT C – TRUSCREEN PRINT OUT


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


ATTACHMENT D - SUS PACKAGE LABELLING (EXAMPLE)


Peal and stick onto TruScreen print out

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 SCHEDULEMAR/2015: Site selection. APR/2015: Signing of Memorandum of UnderstandingAPR/2015: Registration of participating centresMAY/2015: TruScreen TrainingJUN/2015: Project CommencesNOV/2015: Project CompletionDEC/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 STATISTICSRecruitment 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.


truscreen cervical screening system

Documents

clinical trial

general information41

trial chairman

truscreen examination176

multicentre trial

patient id154

medical adviser41

patient withdrawal144