RATIONALE FOR CURRENT STUDY~Identifying women at high risk of having a sPTB and offering treatments and intervention to try and prevent this outcome is a huge priority in clinical practice and in government policy. Continued research in preterm birth is crucial to develop evidence-based practice that can improve our ability to reliably predict women at highest risk and identify those most likely to benefit from screening and intervention.~The PRECISION study will explore the use of a new antenatal test of cervical stiffness to try and improve the recognition of women who may deliver early. Current gold standard clinical practice involves measurement of cervical length (CL) and fetal fibronectin in women known to be high risk for PTB. However recent research suggests these methods could be improved upon and we may be able to recognise women at risk more reliably and at an earlier stage in the pregnancy if we use cervical stiffness assessments.~A licensed, CE-marked, vacuum-aspiration device called the Pregnolia system has been developed to give quantitative cervical stiffness index scores during pregnancy. So far, studies using the Pregnolia system have been undertaken in low-risk pregnancy cohorts. This study will apply these findings to a high-risk population for preterm birth. The PRECISION study will directly compare cervical length measurements and fetal fibronectin results with cervical stiffness, using the Pregnolia system, during the second trimester in women known to be high risk for preterm birth. We will aim to explore the best possible predictive tool kit bundle for sPTB using any combination of these assessments.~We hypothesise that the women who subsequently deliver preterm from this cohort will have had lower cervical stiffness scores during pregnancy. Findings from this exploratory study will help guide future clinical trials that may implement change to how national preterm birth screening is undertaken.~Study Design~PRECISION is a single site prospective, exploratory, cohort study of 60 women with a singleton pregnancy who are high risk for preterm birth.~Participants will be recruited directly from the pre-term birth clinic (PTBC) at Liverpool Women's Hospital (LWH). Once patients have been identified as high risk for preterm birth at their pregnancy booking, they will be sent an appointment to attend pre-term birth clinic. With this appointment letter they shall also receive a patient information leaflet regarding the PRECISION study. At their first attendance to the PTBC in early second trimester they will be invited to participate in the study by a member of the research team. At this point they will receive further verbal information on the study and an opportunity to ask questions. If the woman agrees to participate, they will sign the study specific informed consent form and be registered onto a bespoke electronic data capture system that will generate a unique participant identification number (PIN).~Following informed consent, they will then be asked to provide high vaginal swab and fetal fibronectin swab samples, cervical stiffness measurements (all obtained by sterile speculum examination), and cervical length measurements (obtained via transvaginal ultrasound). These assessments will be carried out at their first visit to PTBC. Further cervical stiffness, fetal fibronectin and cervical length (CL) measurements will be undertaken at their subsequent follow up visits at 2-4 weekly intervals, for a total of three assessments. Prior to collection of vaginal swab samples patients will fill in a brief questionnaire stating if any current medications, recent antibiotic and/or antifungal treatment or sexual intercourse. If the patient has had vaginal sexual intercourse in the last 48 hours, high vaginal swab sample collection will be postponed to a later appointment. At the first study visit, participants will be asked to complete a short questionnaire regarding their experience of the cervical stiffness assessment and the transvaginal ultrasound assessment.~Routinely, transvaginal cervical length scanning is offered at every PTBC appointment. High risk women would be seen every 2-4 weeks from 16 weeks until 24 weeks. Therefore, participants will have all study assessments taken at the same time as their routine CL assessment. If there is evidence of a shortened CL (<25mm) at any point the patient will be treated as per local LWH policy. The participant would not be excluded from the research study and planned assessments would still take place.~Once recruited, participants will remain in the study until delivery and discharge from hospital. We will collect routine clinical data from all participants' notes and electronic hospital records for maternal and neonatal outcomes. All study visits will coincide with routine care and all participating women will receive routine antenatal care throughout their pregnancy as per Saving Babies Lives Care Bundle V2, NICE Preterm Labour and Birth guideline and the North West Regional network preterm birth guideline.~Special Laboratory Procedures~All information relating to laboratory analyses and procedures employed within this study will be detailed in a separate PRECISION Laboratory Management Plan. This will include instruction for the preparation, handling, storage and shipping of samples including required temperatures, aliquots of samples, where they will be stored and how they will be tracked and labelled. All procedures will be detailed in separate protocols which will be included in the Laboratory Manual together with plans in terms of the long-term access and consent for the future use of samples.~LOSS TO FOLLOW UP~If for any reason a participant does not attend planned study visits the research team will contact the participant to attempt to rearrange. If further assessments are not possible the participant will be withdrawn from the research study as detailed in section 4.4. If the study procedures are stopped before the end of the scheduled assessment period, the clinician may contact the participant to request additional information up to the point where the study intervention would be completed.~STUDY CLOSURE~Study enrolment at LWH will be stopped when the total requested number of participants (60) for the study have been recruited. The SMG may recommend that the study be stopped prematurely. In such circumstances of premature termination / suspension of the study, the National Research Ethics Committee (REC) and Health Research Authority (HRA) will be notified according to the standard reporting guidelines.~WITHDRAWAL CRITERIA~We do not have formal stop criteria for the PRECISION study. However, we will establish a Study Management Group (SMG) which will meet at least monthly and will have the authority to recommend a halt to recruitment should there be concerns about patient safety.~In consenting to take part in the study, participants are consented to a speculum examination for cervical stiffness assessment and associated data collection and follow-up on pregnancy outcomes. If voluntary withdrawal occurs the participant should be given appropriate care until discharge.~The critical data in PRECISION study is derived from cervical stiffness measurement. Although participants can refuse examination at any time, refusal to have cervical stiffness measurements result in significant compromise to the study. Therefore, any participant who does not have cervical stiffness measurements would need to be withdrawn from the study.~During the study procedure prior to cervical stiffness measurement, the cervix is inspected for any previously unknown cervical pathology at 12 o'clock position, new vaginal bleeding or visible cervical or vaginal infections. If any of these are present, the assessment cannot be undertaken based on manufacturer guidelines for use of the medical device. The patient would then be withdrawn from the study based on cervical criteria.~Foreseeable reasons where a participant may withdraw from the study generally apply to the additional need for a speculum examination and collection of cervical stiffness measurements and include:~Participant withdraws consent,~Newly diagnosed cervical criteria at time of study procedure~Loss of capacity during the study, and~Any other change in the participant's condition that justifies the discontinuation in the clinician's opinion.~A participant is free to withdraw from the study at any time. In addition, the CI may decide, for reasons of medical prudence, to withdraw a participant. In either event, the Sponsor will be notified and the date and reason(s) for the withdrawal will be documented in the participant source data. If a participant withdraws or is withdrawn, ideally, they should remain in the study for the collection outcome data. Generally, follow-up will continue unless the participant explicitly also withdraws consent for follow-up.~Participants who withdraw from the study for other reasons will be given routine standard care until delivery and will be asked to allow analysis of already anonymised data and collection of pregnancy outcome data. If the participant explicitly states their wish not to contribute further data to the study, collected data will be removed from the study database.~RECRUITMENT~Sample Identification~LWH uses the K2 Athena computer system for maternity notes. All pregnancies booked at LWH will have electronic notes on this system, and all referrals to specialist antenatal clinics (including PTBC) take place through this system. Potential participants will therefore be identified through referrals sent to LWH PTBC via the K2 computer system. These referrals are generated following a pregnancy booking appointment when the patient has risk factors for preterm birth. This referral will be triaged by a member of the PTBC core team, and if the patient is identified as potentially eligible for the PRECISION study a PIS will be posted to the patient regarding the study along with their routine PTBC appointment letter.~At their first attendance to PTBC the clinical team (doctors and midwives) will identify if the patient meets the eligibility criteria, enquire as to whether the PRECISION PIS was received and if the patient is happy to discuss participation further with a member of the research team. If the patient agrees, a member of the PRECISION research team will be contacted to attend PTBC during their appointment to discuss study recruitment. Any potential participants that decline to participate will have routine care as usual, but we will detail the reasons for why they have declined to keep an accurate and accountable recruitment rate for the study.~Informed Consent~On meeting a member of the research team, potential participants will be provided with an additional PIS to refer to, the opportunity to ask questions, discuss study objectives, risks and inconveniences of the study and the conditions under which the study is to be conducted. More time will be offered for consideration of participation if necessary and it will be made clear to the participant that the quality of medical care will not be adversely affected if they decline to participate in this study and they may withdraw from the study at any time.~Once a participant is happy to consent, they will be asked to sign the study-specific Informed Consent Form (ICF) in the presence of a member of the research team. Three copies of the consent form will be collected, the original given to the participant, one placed within the participants hospital notes one held at the CfWHR. The PI will be required to review and sign all consent forms.~The PI will ensure that all members of the research team obtaining consent comply with applicable regulatory requirements, adhering to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Members of the research team will also have received study specific training relating to eligibility screening and the informed consent / registration process and CV's will be reviewed of all team members to ensure adequate experience in gaining consent in a research capacity.~The PIS sent to potential participants has been reviewed by our Liverpool Babies PPI group who assisted on layout, language and formulation of lay explanations to make it easily understood. In addition, previous PIS and consent forms used in singleton preterm birth studies at LWH were reviewed to see what format of information is acceptable for participating women.~Enrolment and Registration~Once a participant has been identified as eligible for the PRECISION study, they will be registered onto the study using an electronic registration platform. Although it will be recommended that participants take a minimum of 24 hours to consider taking part in this study, the provision for allowing participant consent within a shorter period-of-time will be permitted - this is to reduce the number of examinations the patient undergoes, ensuring cervical stiffness assessments will be taken at the same time as routine cervical length screening in PTBC.~Once a participant consents to taking part in the study, they will be registered on a bespoke electronic data capture system that will generate PIN.~STATISTICS AND DATA ANALYSIS~In the following section a brief overview of planned analyses for this study will be set out.~Once informed consent has been gained for participation in PRECISION, participants will be registered onto the study database and a unique PIN will be generated. Participants will be registered onto the study database in accordance with the study registration operating procedures and registration will be performed by authorised PRECISION research staff using an electronic system. This system will be available 7 days per week, 24 hours a day and will be accessed by delegated site staff using a secure password protected website. All research staff will receive comprehensive training on the use of this system, which will be documented and stored in the Investigator Site File (ISF). In the unlikely event that the back-up registration process is activated, participant registration will be performed by the Study Co-ordinator.~Data from the PRECISION CRFs will be entered onto a bespoke study database with extensive data validation checks alerting all missing data to be queried. Missing data will be monitored and strategies will be developed to minimise its occurrence. Central statistical data monitoring will summarise missing or inconsistent data periodically. The study CRF will be approved by the CI and validations will also be made that will cross check the study CRF with the PRECISION study database.~SAMPLE SIZE~The LWH PTBC sees 230 new referrals each year. We anticipate 150 women annually to meet eligibility criteria for our study, and hope to achieve a recruitment rate of 50% from this patient group. Over an 11-month period, we would therefore conservatively expect to recruit 60 women. This would equate to successfully recruiting 5-6 new patients referred to PTBC every month.~As this is an exploratory piece of work a formal sample size calculation has not been performed.~STATISTICAL METHODOLOGY~Initial statistical analysis of the data will involve testing for normality of data variables using the Shapiro-Wilk test. If a normal distribution is confirmed we will proceed with univariate statistical analysis using Fisher's exact test for categorical variables and Student's t-test for continuous variables and results will be presented as percentages and mean ± SD, respectively.~Multivariate analysis will be performed using logistic regression, including cervical stiffness index and other variables related to gestational age, and results will be presented as odds ratios with 95% confidence intervals.~Logistic regression and analysis of receiver operating characteristics(ROC) curves will be performed to evaluate the diagnostic power of cervical stiffness assessments, cervical length and fetal fibronectin measurements. The area under the curve and 95% confidence intervals of these areas will be calculated, as well as aiming to define the best cut-off value for each diagnostic test.~Participant Groups for Analyses Entire observational cohort of 60 high risk women with singleton pregnancies attending preterm birth clinic.~Significance levels As this is an exploratory study no formal levels of significance are set. All statistics presented will be presented alongside 95% confidence intervals so as to give an indication of the level of precision only.~Missing Data The likelihood of missing data is small given the standard procedure in place to manage the study centrally. Final analyses will take place on a complete-case basis with no adjustments made (e.g. multiple imputation) in the case of missing data.~Trigger for Final Data Analyses Analysis of study data will take place once all participant data and samples have been received and processed; with corresponding laboratory data available for analysis.~Data Descriptors Continuous data will be summarised as median, inter-quartile range and ranges. Categorical data shall be summarised as frequencies of counts and associated percentages.~REGULATORY ISSUES~ETHICS APPROVAL A favourable opinion from the UK Health Departments Research Ethics Service NHS REC and the Health Research Authority (HRA) for the study protocol, informed consent forms and other relevant documents has been granted.~The study will be submitted to the proposed research site for Confirmation of Capacity and Capability. The study will be conducted in accordance with the recommendations for physicians involved in research on human subjects adopted by the 18th World Medical Assembly, Helsinki 1964 and later revisions~CONSENT Consent to enter the study must be sought from each participant only after a full explanation has been given, an information leaflet offered and time allowed for consideration. Signed participant consent should be obtained. The right of the participant to refuse to participate without giving reasons must be respected. After the participant has entered the study the clinician remains free to give alternative treatment to that specified in the protocol at any stage if he/she feels it is in the participant's best interest, but the reasons for doing so should be recorded. In these cases the participants remain within the study for the purposes of follow-up and data analysis. All participants are free to withdraw at any time from the protocol treatment without giving reasons and without prejudicing further treatment.~CONFIDENTIALITY The Chief Investigator will preserve the confidentiality of participants taking part in the study and will abide by the Data Protection Act 2018 and the UK GDPR as amended from time to time and any successor legislation in the UK and any other directly applicable regulation relating to data protection and privacy. All members of the research team will have received ICH GCP training and are thus aware of the importance of patient confidentiality. Individual participant medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited.~At time of consent participants will be allocated a unique participant identification number. A key to this information along with consent forms (containing patient identifiers) and pseudonymised CRFs (identified by participant identification number only) will be stored separately in locked filing cabinets, located in secure rooms within the CfWHR, UoL, with restricted keycard access to nominated clinical research/admin staff who work directly for the unit. Data from pseudononymised CRFs will be transferred to a password protected, nominated user restricted access REDCap database that will be housed on a secure server at the UoL. This server will be backed up and maintained in line with institutional compliance regulations for Data Protection and Information Security.~The study coordinator will consistently check that all study documentation stored in the CfWHR is pseudonymised and identifiable only by a unique study identification number (except for signed consent forms, which will be stored in a separate locked cabinet in the CfWHR).~The Chief Investigator will preserve the confidentiality of participants taking part in the study and will abide by the EU General Data Protection Regulation 2016 and Data Protection Act 2018.~QUALITY ASSURANCE AND QUALITY CONTROL OF DATA~Systems of quality assurance, including all elements described in this protocol have been/ will be implemented within relevant institutions with responsibility for this study. QC is applied to each stage of data handling to ensure that data are accurate, reliable and processed correctly.~The study site, facilities, laboratories and all data (including sources) and documentation must be available for GCP audit and inspection by competent authorities or IEC. Such audits / inspections may take place at any site where study related activity is taking place (the Sponsor's site(s), the CfWHR or at any investigator's site including laboratories).~The site staff should assist in all aspects of audit/inspection and be fully cognisant of the Sponsor communication strategy for single and multicentre studies. This includes management systems for the green light process prior to participant recruitment at site.~RECORDS RETENTION~The investigator at LWH site must make arrangements to store the essential study documents, (as defined in Essential Documents for the Conduct of a Clinical Study (ICH E6 (R2), Guideline for Good Clinical Practice)) including the Investigator Study File, until the Sponsor or the CfWHR informs the investigator that the documents are no longer to be retained.~In addition, the investigator is responsible for archiving of all relevant source documents so that the study data can be compared against source data after completion of the study (e.g. in case of inspection from authorities). The investigator is required to ensure the continued storage of the documents, even if the investigator, for example, leaves the clinic/practice or retires before the end of the required storage period. Delegation must be documented in writing. The CfWHR undertakes to store all electronic data related to completed database, except for source documents pertaining to the individual investigational site, which are kept by the investigator only. At the point where it is decided that the study documentation is no longer required; the Investigator will be responsible for the destruction of all site study specific documentation and the Sponsor /CfWHR will be responsible for the destruction of all study related materials retained.~Verification of appropriate informed consent will be enabled by the provision of copies of participants signed ICF being supplied to the CfWHR by LWH (recruiting site). This requires that name data will be transferred to the CfWHR, which is explained in the PIS. The CfWHR will preserve the confidentiality of participants taking part in the study and the UoL is a Data Controller registered with the Information Commissioners Office.~STUDY DISCONTINUATION~If this study is prematurely discontinued (e.g., due to safety) all participants must be informed and the reason for the discontinuation should be written on the end of study form for each participant. If a participant has been withdrawn completely from the study whilst the study is still ongoing, an end of study form should be completed.~INDEMNITY The University of Liverpool professional indemnity and clinical trials insurance will apply as appropriate.~SPONSOR The University of Liverpool.~FUNDING This study is funded by the Harris-Wellbeing Preterm Birth Centre and the Centre for Women's Health Research.~AUDITS The study may be subject to inspection and audit regulatory bodies to ensure adherence to GCP and the UK Policy Framework for Health and Social Care Research (v3.2 10th October 2017).~STUDY MANAGEMENT The day-to-day management of the study will be coordinated through the Centre for Women's Health Research, Department of Women' and Children's Health.~STUDY MANAGEMENT GROUP (SMG) A Study Management Group will be formed comprising the CI, other lead investigators / core study management staff who are central to the day-to-day running of the study. The SMG will be responsible for the day-to-day running and management of the study and will meet at regular intervals throughout the course of the study. The frequency of meetings will be decided by the CI. However it is expected that they should take place at least monthly. This group may consist of the following members of the core research team however all are not required to attend each meeting in person. Compulsory attendance in denoted by a *.~*Chief Investigator~Research Manager~*Co-applicants~Sponsor representative~OVERSIGHT COMMITTEES This study will not convene both a Steering Committee or an Independent Safety and Data Monitoring Committee (ISDMC) as this is a low risk non-interventional prospective cohort study. Oversight will be provided by the SMG and Sponsor.~END OF STUDY The study will end when the last recruited woman has delivered and both herself and her baby have been discharged from hospital, or 1 month after delivery, whichever is sooner and all planned analysis of collected data has taken place.
Preterm birth (PTB), defined as delivery before 37 weeks gestation, is a common complication of pregnancy and affects up to 1 in 10 women in the UK. PTB is the leading cause of neonatal mortality and morbidity with babies born earliest being at the greatest risk. Identifying women at high risk of having a PTB and offering treatments and intervention to try and prevent this outcome is a huge priority in clinical practice and in government policy.~The PRECISION study will explore the use of a new antenatal test of cervical stiffness to try and improve the recognition of women who may deliver early. Current clinical practice involves measurement of cervical length (CL) and fetal fibronectin in women known to be high risk for PTB. However recent research suggests these methods could be improved upon and we may be able to recognise women at risk more reliably and at an earlier stage in the pregnancy if we use cervical stiffness assessments.~A licensed, CE-marked, vacuum-aspiration device called the Pregnolia system has been developed to give quantitative cervical stiffness index scores during pregnancy. This study will directly compare cervical length measurements and fetal fibronectin results with cervical stiffness, using the Pregnolia system, during the second trimester in women known to be high risk for preterm birth. We will aim to explore the best possible predictive tool kit bundle for PTB using any combination of these assessments.