Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05451277 |
| Other study ID # |
At the Heart- MP-37-2022-7935 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
April 1, 2021 |
| Est. completion date |
September 30, 2023 |
Study information
| Verified date |
August 2022 |
| Source |
McGill University Health Centre/Research Institute of the McGill University Health Centre |
| Contact |
Évelyne Vinet, MD, PhD |
| Phone |
514-934-1934 |
| Email |
evelyne.vinet[@]mcgill.ca |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Women with systemic lupus erythematosus (SLE) have a high risk of placenta-mediated
complications, which can lead to substantial cardiac morbidities in affected women and their
offspring. In addition, maternal autoantibodies, which are actively transferred across the
placenta during pregnancy, can affect the cardiovascular health of SLE offspring.
Hydroxychloroquine (HCQ) is effective in preventing adverse pregnancy outcomes in SLE and
might be beneficial in preventing fetal cardiovascular damage mediated by maternal
autoantibodies. However, there are concerns that HCQ might cause maternal and neonatal
cardiac toxicity. A novel imaging technique (i.e. speckle tracking echocardiography), which
allows early identification of cardiac dysfunction, has proven superior to any other in
assessing cardiac function in mothers and neonates experiencing placenta-mediated
complications and in identifying drug cardiotoxicity. Yet, there has been no study using
speckle tracking echocardiography to evaluate the cardiovascular health of pregnant SLE women
and their offspring, as well as the potential adverse cardiac effect of HCQ. Moreover, due to
unavailability of assays, HCQ dosing in SLE is generally done blindly, without checking drug
levels. To fill these key knowledge gaps, the investigators aim to: 1) assess the impact of
placenta-mediated complications on maternal and neonatal cardiac function, 2) evaluate if HCQ
exposure (as measured by whole-blood levels) is associated with maternal and neonatal
outcomes including cardiac toxicity, and 3) determine the effect of maternal autoantibodies
on neonatal cardiac function. Ultimately, our proposal will help optimize reproductive and
cardiovascular outcomes in lupus women and their offspring.
Description:
Women with SLE have a high risk of placenta-mediated adverse pregnancy outcomes (APO),
including gestational hypertension, preeclampsia, eclampsia, small for gestational age (SGA)
neonate, placental abruption, and stillbirth. It is hypothesized that high levels of
circulating anti-angiogenic factors, placental microparticles, and other soluble mediators
cause endothelial dysfunction and lead to cardiovascular diseases (CVD) in women with APO. In
women with SLE, CVD is the leading cause of death, accounting for almost half of all
deaths.Until now, studies have been unable to identify the cause of increased CVD in SLE
women, despite accounting for SLE disease activity, damage, and drugs. Given the huge burden
of CVD in SLE, it is unfathomable that no one has, to date, comprehensively examined the
relationship between APO and CVD risk in SLE women.
Importantly, the offspring of mothers with placenta-mediated complications also have an
increased CVD risk and in SLE offspring, in-utero exposure to maternal autoantibodies might
further contribute to increased CVD risk.
Hydroxychloroquine (HCQ), the cornerstone drug in SLE treatment, may prevent SLE flare during
pregnancy and reduces the risk of APO. However, HCQ may pose cardiotoxicity. HCQ dosing is
done by weight but surprisingly, drug level monitoring is almost non-existent in Canada,
although it is increasingly championed by key opinion leaders in the US and Europe. Lack of
drug level monitoring is particularly concerning during pregnancy, given potential risks to
mother and baby for adverse outcomes related to under or potentially overdosing. The
incidence and prevalence of HCQ cardiotoxicity are not known and it is likely to be an
under-diagnosed complication as patients are not systematically screened. Furthermore, data
are urgently needed to address cardiac safety in neonates exposed to HCQ.
To assess cardiac function (i.e., myocardial contraction and relaxation), the investigators
will use global longitudinal strain (GLS) measured by speckle tracking echocardiography
(STE). GLS has superior prognostic value to conventional measures such as the left ventricle
ejection fraction (LVEF) for predicting major adverse cardiac events and provides incremental
prognostic information beyond the traditional CVD risk stratification tools. Moreover, GLS
assessed by STE has most consistently detected early myocardial changes during therapy and
appears to be the best measure of early drug cardiotoxicity, predicting future reduction in
LVEF or heart failure.
The investigators will test the hypothesis that SLE women with APO have higher frequency of
impaired myocardial strain versus SLE women without APO. The investigators will also evaluate
the hypothesis that exposure to maternal autoantibodies during pregnancy (ie anti-Ro/La and
aPL) is associated with impaired myocardial strain in neonates (versus unexposed neonates).
Another hypothesis is that maternal and cord HCQ levels correlate with impaired myocardial
strain in mothers and neonates respectively, potentially following a J-curve relationship
(i.e. lower HCQ levels failing to be cardio-protective against maternal autoantibodies and
higher HCQ levels leading to cardiotoxicity).
Primary aims: Using STE, the investigators will: 1) Assess the impact of placenta-mediated
complications on maternal and neonatal myocardial strain, 2) Determine the effect of maternal
autoantibodies on neonatal myocardial strain, 3) Evaluate if maternal and cord HCQ levels are
associated with maternal and neonatal myocardial strain.
Primary deliverables: The investigators will develop: 1) Innovative risk stratification
approaches for CVD in SLE women, 2) New tools for identifying subclinical cardiac involvement
in offspring ex-posed in utero to APO, maternal autoantibodies, and/or HCQ, 3) HCQ
cardiotoxicity screening strategies in SLE women and offspring, and 4) Novel therapeutic drug
monitoring approaches for efficacy and safety of HCQ in pregnancy. Furthermore, the knowledge
gained by this study will allow an investigator to further assess the effects of APO in other
high-risk pregnancies.
Methods:
1. Patients with SLE At the time of the Lupus in prEGnAnCY (LEGACY) Biobank baseline visit,
the investigator will recruit 30 pregnant women with SLE, without a prior history of
placenta-mediated APO, and without preexist-ing CVD, hypertension, and non-gestational
diabetes, which will form the "SLE group". LEGACY includes all intrauterine singleton
pregnancies, before the 16th gestational week in SLE women, 18-45 years, regardless of
SLE disease manifestations, level of disease activity, and medication exposures. At
baseline, the investigator collects detailed data on maternal demographics, obstetrical
history, co-morbidities, lifestyles, SLE activity and damage measures, as well as
medications, including detailed information on HCQ use. LEGACY also measures data on
relevant clinical parameters (e.g. blood pressure, random urine protein/creatinine
ratio, etc) and maternal autoantibodies (e.g. aPL, anti-Ro/La). In addition, samples
(serum, plasma, DNA) are biobanked at the Research Institute of McGill University Health
Centre. Patients are reassessed by the investigator in the 2nd (between 20-24 weeks) and
3rd (between 30-34 weeks) trimesters, as well as in the postpartum (8-12 weeks after
delivery). At these visits, clinical information is updated and occurrence of
placenta-mediated APO is ascertained according to accepted international definitions.
2. Patients without SLE The investigators will recruit 3 groups of non-SLE women with a
singleton pregnancy, without preexisting CVD, hypertension, non-gestational diabetes,
nor prior history of placenta-mediated APO and matched 1:1 on age and ethnicity to SLE
women. The first group, the "baseline control group", will consist of 30 pregnant women
at less than 16 gestational weeks recruited during their first trimester visit at the
Royal Victoria Hospital (RVH) obstetric clinic. The investigators will also identify 30
women with placenta-mediated APO as well as 30 women without any placenta-mediated APO
upon admission for surveillance, delivery, and/or during the immediate postpartum at the
RVH birth centre. These women will respectively constitute the "control group with APO"
and the "control group without APO". For all non-SLE subjects, the investigators will
obtain data on maternal demographics, obstetrical history, co-morbidities, lifestyles,
drugs, and clinical parameters, similarly as for LEGACY subjects. An obstetrical
medicine specialist has easy access to potentially eligible non-SLE subjects and will
facilitate recruitment. Despite the pandemic, the investigators do not anticipate issues
in recruiting SLE and non-SLE pregnant patients as prenatal care and hospitalizations
for delivery are essential medical services maintained even at the worst of the
pandemic. Pregnant SLE women are highly motivated for participation in research projects
(e.g. LEGACY participation rate is 97%). The investigators will accommodate subjects by
scheduling assessments with routine pregnancy visits. Strict safety measures will be
implemented to minimize the risk of nosocomial COVID-19.
3. HCQ levels in mothers and offspring As previously mentioned, a key team member has
already developed and is in the process of validating a method for whole-blood HCQ
quantitative analysis (de-tails at www.agilent.com). Once validated, this method will go
through the regulatory process for its full clinical implantation and approval for
therapeutic drug monitoring. In short, this novel methodology uses whole-blood samples
prepared by protein precipitation extraction followed with Agilent Captiva EMR-Lipid
clean-up, then analyzed by triple quadrupole liquid chromatography mass spectrometry.
This method provided a reliable solution with excellent quantitation accuracy (100±5%)
for HCQ levels. Maternal whole-blood samples will be collected at the time of the
echocardiography, while cord blood samples will be obtained at the time of delivery.
4. Echocardiographic assessment Myocardial imaging, including GLS assessment, will be
performed at less than 20 gestational weeks in the SLE and baseline control group. In
the SLE group, cardiac imaging will be repeated both in mothers and offspring in the
immediate postpartum, up to 72 hours after delivery. Similarly, in the control groups
with and without APO, echocardiography will be performed in mothers and offspring until
72 hours postpartum.Transthoracic echocardiogram will be done by an investigator, who
will be blinded to maternal SLE and APO diagnoses, as well as maternal autoantibodies
status, using a "Philips-Epiq7c" machine. Images will be obtained according to
established guidelines.19 Echocardiography will be performed at bedside in mothers and
neonates, after delivery at the RVH birth centre. Of note, all pregnant SLE women
enrolled within LEGACY deliver at the RVH. The investigator in charge will perform a
comprehensive echocardiographic examination of mothers and offspring to determine
conventional measures of ventricular function, including a complete 2-dimensional (2-D)
and colour flow-Doppler assessment. The LEVF will be calculated using Simpson's method.
An investigator in charge will perform a blind review of all traditional
echocardiographic assessments. 3-dimensional (3-D) echocardiography of right ventricle
(RV) and left ventricle (LV) volumes will also be acquired. GLS will be measured using a
2-D and 3-D STE software (i.e. TomTec Arena). For evaluation of strain, the endocardial
border will be traced, at end-systole in the appropriate imaging plane. Peak GLS will be
measured by the software using an average of 2 consecutive cardiac cycles. Measures will
be repeated twice to calculate intra-observer intraclass correlation coefficient (ICC).
An investigator will blindly review STE assessments to calculate the inter-observer ICC.
Statistical analyses
1. Impact of placenta-mediated APO on maternal & neonatal GLS (aim 1) In SLE mothers, the
investigators will compare GLS in early pregnancy versus the postpartum. The
investigators will further compare GLS in SLE with and without APO, both in early
pregnancy and in the postpartum. The investigators will also determine if GLS is
different in SLE versus controls in early pregnancy and in postpartum, stratifying for
APO status.
In offspring, the investigators will compare mean GLS in children born to mothers with
APO versus those born to mothers without APO, stratifying for maternal SLE status. To
compare the GLS between groups, the investigators will calculate the mean (with standard
deviation) and median (with interquartile range). Comparisons between groups will be
performed using either Student's t-test (for means) or Mann Whitney U test (for
medians), depending on data distribution.
2. Maternal autoantibodies & neonatal GLS (aim 2) In SLE offspring, the investigators will
determine if GLS differs among those exposed to maternal autoantibodies (assessing
respectively anti-Ro/La and aPL) versus unexposed offspring. The investigators will
explore stratification by quartiles of HCQ cord blood levels. Comparisons between groups
will be performed using either Student's t-test (for means) or Mann Whitney U test (for
medians), depending on data distribution.
3. Association of maternal and cord blood HCQ levels with maternal and neonatal GLS (aim 3)
In SLE mothers, the investigators will perform a univariate linear regression analysis
with GLS as the dependent variable and maternal HCQ levels as the independent variable.
The investigators will assess the possibility of a J-curve relationship by adding a
quadratic term to the regression analysis and determine goodness of fit for both models
(with and without quadratic term). In a sensitivity analysis, the investigators will
explore the effect of cumulative HCQ drug exposure on GLS.
In offspring, the investigators will perform a univariate linear regression analysis
with GLS as the dependent variable and cord HCQ levels as the independent variable. The
investigators will also assess the possibility of a J-curve relationship by adding a
quadratic term to the regression analysis and determine goodness of fit for both models
(with and without quadratic term). In a sensitivity analysis, the investigators will
restrict the analysis to neonates born to SLE mothers without anti-Ro/La and aPL
antibodies. The investigators will also explore the impact of cumulative maternal HCQ
drug exposure during pregnancy on neonatal GLS.
4. Power calculation Based on estimates of mean GLS and standard deviations from prior
studies, the proposed sample size will allow the investigators to detect a difference in
mean GLS of at least -2.2% when comparing any groups (including between SLE groups with
and without APO, assuming an APO incidence of 30%), with 0.80 power and 2-sided alpha of
0.05.
This research will lead to a novel approach for early risk stratification of SLE women and
offspring at high risk of CVD. Identifying those at greatest risk is critical to implement
preventive strategies and optimal management of modifiable CVD risk factors. The findings
will inform efforts to develop a SLE-specific CVD risk prediction tool accounting for
pregnancy history, using data from the SLICC Inception Cohort. Determining that maternal
autoantibodies are associated with subclinical cardiac disease in offspring will not only
offer insights into mechanistic pathways but offer the opportunity to examine therapeutic
agents, such as HCQ, and improve management to reduce long-term CVD risk. This study will
highlight the importance of monitoring HCQ levels in pregnancy. As virtually all SLE
pregnancies (and a large number of rheumatoid arthritis and other rheumatic disease
pregnancies) are exposed to HCQ, this study will provide critical data to inform the conduct
of future studies in several populations of pregnant women with rheumatic diseases. The novel
findings will be highly relevant to other high-risk pregnancy populations. Myocardial strain
might prove not only to be a sensitive marker of cardiac involvement, but also a potentially
sensitive outcome measure, responsive to therapy. Thus, findings from this study could help
the conduct of future clinical trials and the methodology could be applicable to the
assessment of subclinical cardiac involvement in other rheumatic diseases (e.g. systemic
sclerosis). The investigators' close links with the Canadian Network for Improved Outcomes in
SLE (CaNIOS) and SLICC will allow the investigator to lead the way nationally and
internationally in establishing further studies to improve reproductive and cardiovascular
outcomes in SLE.
