Clinical Grade MIS Device for Cervical Assessment to Predict Preterm Birth

The studies will be undertaken at the Jessop Wing (JW) Maternity Unit of the Royal Hallamshire Hospital, a tertiary referral unit with annual birth statistics of approximately 8000 births per annum. The JW receives in utero transfers from > 6 other hospitals in South Yorkshire and houses the regional neonatal intensive care unit with high dependency care facilities equipped to deal with extremely premature births, including those born at gestational ages borderline for viability (23-26weeks). The unit is therefore suited for the care of women at high risk of premature delivery and is well suited to house this study. The clinician on the core research team for this application also accepts referrals for high risk antenatal care and surveillance of women most at risk of premature delivery from colleagues in referring hospitals.

To reach this objective, the Investigators will package the project into three work packages (WP) with target milestones over 36 months. The time frames for the study phases are outlined below.

WP1. DURATION - 30 MONTHS, M1-30. LEAD J. HEALEY

Objectives:

• To recruit high-calibre research staff (Postdoctoral Research Associate Clinical Engineer and Clinical Research Fellow) at project initiation.
• To refine/optimise the hardware and software of the MIS device to enable a clinical grade version - the MIS Mark 2 device (in collaboration with Arrow Technical).
• To apply for MHRA regulatory approvals for a device that can be employed for follow-on multicentre studies, towards eventual CE Marking post-project.

Outline of work strands in WP1. Improvements on current MIS 1 device prototype that will be addressed during this work package (M1-M9) include the following:

• Removal of measurement artefacts
• Removal of probe handling sensitivity from perturbations of the electric field around the probe
• Reduction in thermal drift by better choice of materials and coil assembly and the use of "mechanical chopping" of the magnetic field
• Reduction of power dissipation in the probe in order to improve stability 5. Improving the ruggedness of the probe to cope consistently with clinical use 6. Fractionally reducing the probe diameter.

These will culminate in refinements to the device hardware and software (M8-9). The Investigators will also simultaneously consolidate the technical documentation, which have been systematically collected during the development of the MIS Mark 1 device (M1-M18), and submit an application to the MHRA for regulatory approvals by M19. Following iterations with the MHRA they anticipate obtaining final approvals by the MHRA by the end of this workpackage (M30).

PPI Input to WP1

• The Investigators will schedule their first PPI meeting in Month 3 - this meeting will include an induction programme for new PPI members, as well as a refresher session for current PPI members. The PPI group will deliberate on the research plan and the participant information leaflets and consent forms for the clinical studies that will be submitted for National Research Ethics Committee approvals.

o This PPI meeting has successfully held on 27 April 2017

• A second PPI meeting in Month 11 will review project progress, consider the Mark 2 MIS device and advice on the planned submission to the MHRA.

WP1 Deliverables:

• Prompt initiation of project following successful pre-project employment of PDRA and Clinical Research Fellow.
• 1st PPI meeting Month 3.
• Manufacture of high-performance Mark 2 MIS cervical device by M10
• 2nd PPI meeting Month 11
• Submission of initial application for regulatory approvals by the MHRA by M19
• MHRA Regulatory approvals secured by M30 WP2. DURATION - 30 MONTHS, M 1- 30. LEAD PROF DILLY ANUMBA

Objectives:

During this phase, the Investigators will conduct clinical experimental studies to determine the predictive potential of the MIS Mark 2 device for preterm birth (PTB) in a cohort of asymptomatic women at risk of PTB (previous history of PTB, AHR) attending for pregnancy care (n=100), and another cohort of women (n=100) presenting to labour ward between 20-34 weeks with symptoms of preterm labour (regular uterine contractions - > 1 contraction every 10 minutes - but cervix less than 4 cm dilated, SYM). The rationale for sample size estimates is clarified later on this protocol.

Outline of work strands in WP2:

This WP will overlap with WP1 to ensure that technical project development occurs in tandem with the preparation for, and execution of, clinical experimental studies.

During this WP the Investigators will:

• Obtain research ethics and governance approvals (M1-M6).
• Generate preliminary data (M7-M18) that will be employed to: a) apply to the MHRA for regulatory approvals, and b) optimise the probe hardware and software further, and
• Conduct experimental studies on the cohorts detailed above (M8-M30) - recruit and study asymptomatic HR cohort (n=100) and symptomatic cohort (n=100) from M8 -M30 (22 months). In addition to standard care, the women will have an ultrasound scan to assess cervical length, vaginal swab specimen collection for fetal fibronectin determination and microbiological studies and MIS assessment at each of two study visits. Women with abnormal cervical cytology in the previous 3 years or with signs of ongoing cervical infection will be excluded from the studied.

Study conduct details:

• Target population and sample selection: Asymptomatic high-risk women. These participants (≥ 16 years of age) will have had no signs of cervical infection, no previous cervical surgery, and will have had a normal cervical smear within the previous 3 years. Prospective participants will be approached at their first hospital antenatal visit. The study will be explained and study materials provided. The participants will be asked to contact research staff by telephone or through their community midwife, or at the time of the participant's next attendance to the prematurity clinic or ultrasound scan appointment if the women wishes to participate. Written informed consent will then be obtained by research staff who will also conduct the two study visits. Women will be scheduled to attend for MIS measurement at 20-22 weeks, to be repeated at 26-28 weeks. This measurement will be taken at the same time as the routine examination which the participants receive when they attend the prematurity clinic. At each study visit the patient will undergo a vaginal examination. Triple high vaginal swabs will then be taken for bacteriology and fetal fibronectin. The sterile magnetic impedance probe will then be introduced, data being captured automatically by pressing the data capture button on the handle of the device. A transvaginal scan will also be performed to measure CL. The average duration of this assessment, from obtaining the swabs to completing the ultrasound scan, is about 7 minutes.

The above procedure will be carried out at each of the two study visits planned. Women attending the prematurity clinic are seen on average every two to three weeks. Consequently, cervical magnetic impedance spectroscopy measurements will not need to be measured at every hospital visit.

Symptomatic pregnant women. These women (≥ 16 years of age) will be approached when the participant attends the labour delivery room or triage with symptoms of preterm labour as detailed above. As a matter of clinical routine these women receive a speculum examination, triple vaginal swabs taken, and fetal fibronectin and cervical length scans as indicated. The study will be explained to them and study materials provided. The participants will be asked to contact research staff by telephone or through their clinical midwife if the participants wish to participate. The participant will be given time to decide. If the participant agrees to take part, written informed consent will then be obtained by research staff who will also conduct the MIS study. If clinical assessments have not already been performed by the time of obtaining consent the participant will be carried out at the same time

Inclusion criteria

• ≥ 16 years of age
• no signs of cervical infection
• no previous cervical surgery
• had a normal cervical smear within the previous 3 years
• identified as asymptomatic high-risk antenatally (Asymptomatic high-risk women participants)
• Symptoms of preterm labour (Symptomatic Pregnant women participants)

Exclusion criteria

• < 16 years of age
• signs of cervical infection
• previous cervical surgery
• no cervical smear within previous 3 years
• not identified as symptomatic high-risk antenatally (Asymptomatic high-risk women participants)
• No symptoms of preterm labour (Symptomatic Pregnant women participants)