Clinical Trial Details
— Status: Recruiting
Administrative data
NCT number |
NCT04508582 |
Other study ID # |
IRAS 281197 |
Secondary ID |
|
Status |
Recruiting |
Phase |
|
First received |
|
Last updated |
|
Start date |
November 25, 2020 |
Est. completion date |
July 31, 2025 |
Study information
Verified date |
April 2024 |
Source |
Queen Mary University of London |
Contact |
Alice P Christensen |
Phone |
020 7882 8235 |
Email |
a.p.christensen[@]qmul.ac.uk |
Is FDA regulated |
No |
Health authority |
|
Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
Preeclampsia is a multi-system vascular disease which affects 2-5% of pregnancies. It is also
a risk factor for the development of cardiovascular disease later in life and a number of
functional and structural cardiac changes have been found in this population of patients.
In mouse models disruption of a group of immune cells, neutrophils, has led to alteration of
the placenta and offspring consistent with those seen in preeclampsia. These mice also have
an abnormal cardiac function and structure (Nadkarni et al 2016). The investigators
hypothesis that this may also occur in humans.
This study aims to intimately link the maternal immunological and vascular components of
cardiac dysfunction in women preeclampsia. The investigators hypothesise that in preeclampsia
activated neutrophils may affect maternal immune system thus leading to myocardial injury and
altered cardiac function. The study intends to identify the mechanisms by which the maternal
immune system (focusing on neutrophil and T-cell subsets) affects cardiac function in women
with preeclampsia. Specific aims to be addressed are:
Aim 1: To correlate specific neutrophil phenotype(s) and function to cardiac function in
women with preeclampsia during pregnancy
Aim 2: To test whether specific activated neutrophil phenotype persists postpartum and
whether this neutrophil phenotype correlates with cardiac function in women with preeclampsia
postpartum
The study population will comprise of 3 groups:
1. Normotensive pregnant (~33 patients)
2. Pregnancy-induced hypertension (PIH; New-onset hypertension after 20 weeks without
proteinuria; ~33 patients)
3. Preeclampsia (~34 patients)
Cardiac function will be evaluated using cardiovascular magnetic resonance, echocardiography
and cardiac markers in the blood. The participants immune system will be assessed from blood
samples looking at the immune cells, hormone levels and inflammatory and non-inflammatory
mediators.
The secondary research objective is to investigate whether changes in the immune system and
cardiac function in participants is persistent after delivery. Therefore participants will
have scans and blood tests both antenatally and at 3 months postnatally.
By identifying key changes in immune cell type and function with cardiac abnormalities in
women with preeclampsia, data obtained from this study could provide novel insight into how
the maternal immune system influences cardiac changes in normal and preeclamptic pregnancies.
Identifying such links could pave the way for future therapeutic targets.
Description:
Study design
The overall aim of the clinical observational study is to determine whether the
pro-inflammatory immune cell phenotype observed in women with preeclampsia (PE) can be
correlated to cardiac function during and after pregnancy and in the postpartum period .
The study team will comprise of Dr Alice Christensen (PhD candidate), who will consent
patients within the study group and carry out the clinical and laboratory aspects of the
study; Dr Suchita Nadkarni (primary supervisor) who will oversee and train Dr Christensen on
all basic science aspects of the study; Prof Steve Thornton and Dr Elena Greco (clinical
supervisors) who will be the obstetric leads on the study; Consultant cardiologists will
include Dr Neha Sekhri who will be primary contact for any cardiac issues, Dr Anna Herrey ,
who will oversee the analyses of imaging aspect of the study and Dr Kate Von Klemperer who
will liaise with and advise Dr Christensen at both The Royal London and Barts Hospitals
regarding echocardiography (echo). To this end, ~100 pregnant women will be recruited from
The Royal London Hospital.
The study population will comprise of 3 groups:
1. Preeclamptic patients (34 patients)
2. Pregnancy-induced hypertension (PIH; 33 patients)
3. Healthy pregnant women (33)
Normotensive and PIH patients will be matched for gestational age with PE patients.
Echocardiography and non-contrast cardiovascular magnetic resonance (CMR) studies will be
carried out in all patients in the study upon enrolment and 3-months post partum, on the
assumption that any physiological cardiovascular changes related to pregnancy will have
resolved by then. Dr Anna Herrey - a leading expert in CMR in pregnant women will over-see
the image analyses in the study. Dr Herrey has recently published a paper outlining the
safety of carrying out CMR in pregnant women and the comparative resolution without the use
of gadolinium contrast (Herrey et al 2019). Cardiac function will be assessed by
echocardiography examination measuring ejection fraction, strain and diastolic function (as
well as pulse wave velocity). Myocardial tissue characteristics will be assessed with
non-contrast CMR (T1 and T2 mapping and full volumetric assessment, the gold standard for LV
function analysis(Bellenger et al 2000 and Grothues et al 2002)). Any patient within the
study group who demonstrates abnormal cardiac changes at 3-months post partum will be
referred to Dr Sekhri for a 6-months follow-up (under NHS care at this time point). All
cardiac scans will be carried out as an outpatient at Barts Hospital except for women with
severe PE where the echocardiography will be carried out at bedside, upon admission to the
ward. Thus, these women will not have CMR studies at enrolment but will be invited to attend
the follow-up at 3 months for CMR and echocardiography studies.
Time- matched blood samples will be taken from patients to assess immune cell phenotypes.
Plasma samples will be collected for the analyses of cardiac specific factors (BNP, troponin)
as well as measurement of steroid hormones (progesterone and oestradiol), and soluble
inflammatory and anti-inflammatory mediators. In order to limit bias within the study, all
CMR image analyses (done by Dr Herrey) will be blinded. Dr Sekhri will be available for
second reporting to assess interobserver variability of the CMR studies. Should any
difference become apparent between early- and late-onset PE (PE which develops before and
after 34 weeks gestation, respectively), sub-groups will be analysed within the PE group.
This initial pilot study will inform power calculations for further studies in early and late
onset disease.
Study procedures
Follow-up procedures
All patients recruited to the study, except those with severe PE, will be followed up as
outpatients at The Royal London and will be asked to attend a hospital visit at Barts
Hospital for CMR studies.
Participant withdrawal
Participants will have the option to submit a written request to be withdrawn from the trial
at any stage. Participants will also have the option to withdraw consent from further
participation in which circumstance no further data will be collected for inclusion. In the
unfortunate event that a participant loses capacity, information gathered will continue to be
used but no further data will be recorded.
The investigators will also ask participants if they can retain their contact information so
that the investigators may contact them to take part in future research related to to current
study. This request will be asked on the consent form.
End of Study Definition
The end of the study will be defined by achieving the proposed patient numbers per patient
group (outlined above).
Statistical considerations
As this will be a pilot study the investigators cannot perform power calculations on the
number of patients needed. the numbers for each patient group have been chosen based on the
realistic numbers of patients that they believe can be recruited over the initial 1 year
period and subsequent follow-up studies on these patients.
Method of analysis
With the support of our local NIHR bioinformatics and bio-repository facility
(http://www.whri.qmul.ac.uk/core-facilities/nihr-bioinformatics-and-bio-repository), multiple
parameters will be analysed using multiple group comparisons (ANOVAs) to increase power. In
order to limit bias within the study, all CMR image analyses (done by Dr Herrey and Dr
Sekhri) will be blinded, and interobserver variability will be measured.
The investigators will use flow cytometry to analyse immune cell phenotype. This is a
well-established method. Dr Nadkarni's laboratory has access to a flow cytometry core
facility, which has machines that can identify up 12 phenotypic markers on any given cell.
Moreover, Dr Nadkarni, the Chief Investigator, and her group, have extensive experience in
immune cell phenotyping using this method. The key advantages are:
1. It is the gold-standard for immune cell phenotyping
2. A minimal amount of blood are needed (max 200μls)
3. Antibodies are commercially available and have been extensively validated by ourselves
and others
4. Dr Nadkarni has developed a high throughput method to analyse many samples at once,
thereby minimising handling error
All samples will be processed an analysed within 1 hour of sample collection to minimise
degradation of proteins on the surface of the immune cells.
The investigators also propose to look at circulating factors in the plasma and this will be
carried out using commercially available ELISA kits.
The primary endpoint will be to determine whether there is a correlation between aberrant
immune cell phenotypes and abnormal cardiac function within our preeclampsia patient cohort,
compared to normal healthy and PIH groups. Furthermore, analyses will be carried out to find
statistically significant cardiac functional and phenotypic differences between our
preeclamptic and PIH patient cohorts, which will improve our understanding of cardiac
function between the patient groups.
Ethics
Application for the current study is pending following submission. Informed consent will be
obtained and recorded as described as above. Allowances for special groups are detailed
above.
Incidental Findings
Should any incidental findings of clinical significance arise during the course of the study,
the participants GP and clinical care team will be informed. Consent to contact the GP will
be sought during the enrolment process.
Annual Safety Reporting
The CI will send an Annual Progress Report to the REC and the sponsor using the HRA template
on the anniversary of the REC "favourable opinion".
Data management
All data generated will be stored within an Excel spreadsheet combining clinical and lab
data. The spreadsheet will be password protected stored with a secure hard drive on a
protected computer. Access to the password and data will be on a strict need-to-know basis. A
full audit trail will be in place.
Source Data
Source data for this study will comprise of initial diagnoses of preeclampsia or pregnancy
induced hypertension, which will be obtained from the obstetric care team, lead by Dr Elena
Greco at the Royal London. These will be in the form of blood test results and/or scan images
of the pregnancy.
Subsequent source data will be CMR images taken at the initial time point (diagnoses of
preeclampsia and gestational age-matched controls) and follow-up CMR image data at the 2nd
time point of the study (3 months post-partum). In addition to CMR images, source data will
also be obtained from the laboratory phenotyping of blood samples taken from patients at the
time points mentioned above.
Investigators who are directly involved with the study will have access to the source data.
In some cases, where it is deemed best for the patient and their ongoing care, clinicians may
seek advice from other experts, which may require their access to the source data.
Confidentiality
The investigators will undertake pseudorandomisation, whereby the patient is only be
identifiable by their hospital number. As this will be a follow-up study, the investigators
will need to link the patient and so this study will not be completely anonymised.
Record retention and archiving
The study data and documentation will be archived in accordance with the relevant regulatory
requirements and site SOPs.
A unique alphanumeric patient identifier will be allocated to each participant at the start
of the study. Data will be stored using the unique participant identifiers on a secure
database. Data will not be stored on personal computers. Confidential documents will be
stored in a locked cupboard located in a secure room. Clinical notes will be handled
according to trust protocol. The Data Protection Act and the NHS confidentiality code of
practice will be adhered to throughout this study. Data may be shared with members of the
clinical team to allow ongoing clinical care.
GCP guidelines require that the investigator or the institution maintains all Case Report
Forms and all source documents that support the data collected from each participant plus all
trial documentation. Measures will be taken to prevent accidental or premature destruction of
these documents. Essential documents must be retained for at least 20 years. It is the
responsibility of the sponsor to inform the investigator when these documents no longer need
to be retained. If the responsible investigator retires or leaves the institution
responsibility for the documentation must be transferred to a person who will accept their
custody
Sample preparation and collection
Blood samples to assess immune cell phenotypes will be collected from patients who have read
the information sheet and signed the consent form. on the day of the cardiac MRI. A maximum
volume of 15mls will be taken from the patient at any one time and collected into sodium
citrate tubes.
Laboratory procedures
The majority of the blood samples will undergo phenotypic analyses using the flow cytometry
method. Briefly, 50 microlitres of blood will be labelled with commercially-available
antibodies that are conjugated to flurochromes that can be detected by lasers on the flow
cytometer. Specialised software will enable the analyses of the assessment of phenotypic
markers that are expressed on immune cells.
The samples will also be isolated for specific immune cell including neutrophils and T-cells,
which will be stored in a secure -80oC freezer and may be subsequently used for genetic
testing, including next generation and whole genome sequencing. Such deep sequencing will
allow us to assess genetic changes that may occur alongside the phenotypic changes in the
immune cells.
Plasma will also be collected from these samples to assess circulating factors, to be
assessed by commercially-available kits.
Sample storage and transfer
Blood samples will be taken by the Research Fellow, Dr Alice Christensen, at Barts Heart
Centre, where the Cardiac MRIs are to be carried out. Samples will be stored in an NHS fridge
until transfer to laboratory. Barts Heart Centre is a maximum ten-minute walk to the William
Harvey Research Institute where the laboratory is based. Samples will be transferred by Dr
Christensen to the laboratory using secure sample transfer boxes to be brought to the
laboratory. All blood samples will be processed within one hour of collection.
Safety reporting
Due to the observational nature and design of this study, safety reporting of adverse events
will not occur.
Monitoring and auditing
The Sponsor or delegate retains the right to audit any study, study site or central facility.
In addition, any part of the study may be audited by the funders where applicable.
On-site monitoring will be performed as per the study monitoring plan. Monitoring will
include source data verification.
Monitoring of the centre may be undertaken by a trained study monitor or monitors, to verify
the study documentation.