Abstract
Contract No.: 305823; EU contribution: € 5,998,984; Total costs: € 7,766,109.60; Starting date: 01/01/2013; Duration: 72 months
Background and Objectives
Severe, early-onset fetal growth restriction (FGR) affects 11,000 babies annually in the European Union (EU). In most cases, reduced uterine blood flow restricts substrate delivery to the fetus, a condition called placental insufficiency. Fetal growth slows or can cease well before the time of normal birth. There are no therapies that improve fetal growth in utero. Current management of severe early-onset FGR involves extremely preterm delivery of the fetus (before 28 weeks of gestation), before death occurs in utero, with the aim of minimizing irreversible organ damage, particularly to the brain. This adds additional risks to the baby from extremely preterm birth, with its own attendant short- and long-term complications; affected neonates suffer intracranial hemorrhage, chronic lung disease, and cerebral palsy, with heart disease and diabetes as adults. Furthermore, FGR may be detected while the fetal weight is far below 500 g, a situation considered by many to be nonviable. From cohort studies and local data, we estimate that the cumulative stillbirth/morbidity/neonatal mortality rate in pregnancies affected by severe early-onset FGR is between 65% and 80%.
Recent improvements in the care of premature growth-restricted neonates mean that more neonates survive delivery, but at great cost. Survival studies suggest, however, that even modest increases in birth weight (e.g., from 500 to 600 g) and gestation at delivery (e.g., from 26 to 27 weeks) are associated with significant improvements in mortality and morbidity. Improving uterine blood flow is key and vascular endothelial growth factor (VEGF) is important to achieve this. In preclinical animal models, EVERREST consortium partners have shown that local VEGF gene transfer to the uteroplacental circulation using adenovirus vectors increases uterine blood flow, attenuates constriction of uterine arteries, and increases angiogenesis; these changes result in improved growth of severely growth-restricted fetuses.
The aim of the EVERREST project is to translate these findings from bench to bedside by developing the first clinically applicable evidence-based therapy that could improve perinatal outcome in severe early-onset FGR.
Approach and Methodology
In order to meet this overarching aim, three key streams of work are ongoing. At the outset, we undertook a thorough study of the bioethics of the EVERREST trial and intervention. The study included a review of the literature on gene therapy, experimental treatment of pregnant women and fetal medicine research to clarify relevant ethical, legal, and regulatory issues, and a qualitative interview study with stakeholders and parents of babies affected by severe early-onset FGR. The second work stream involves completion of a reproductive toxicology program: first, in perfused human placentas ex vivo and, second, in rabbits to study the biodistribution of the adenoviral vector after injection into the maternal uterine artery and the effect on the mother and offspring.
On receipt of ethical and regulatory approval, we then aim to perform an uncontrolled, open-label, dose-finding phase I/II (to mother and baby) study in 15 and up to 27 pregnancies affected by severe early-onset FGR of maternal VEGF growth factor therapy using an adenoviral vector, delivered to the maternal uterine artery using minimally invasive techniques. The primary endpoint of the study will be safety and tolerability. Secondary endpoints relate to efficacy by measuring improvements in uterine volume blood flow, fetal growth and gestational age at delivery, and a composite outcome for fetal and neonatal mortality. Outcomes and morbidity will be compared with data from untreated affected pregnancies; these cohort data are currently being generated in the prospective case study that has ethical approval at EVERREST clinical sites in the United Kingdom, Germany, Spain, and Sweden.
Main Findings
Bioethics study
A literature review investigated two key questions: first, whether it is ethical to treat a pregnant woman with a potentially risky treatment when she herself has no benefit from the treatment but it may improve the health and survival prospects of the unborn baby. The review concluded that treatment of the unborn for its own benefit is permitted. The second question considered was whether it is ethical to treat this condition of the unborn baby who may otherwise have died but, with the treatment, may be born with a serious disability. It also addressed the psychological burden of the woman when making her decision in favor of or against the new treatment. The literature review concluded that there was a need to interview women and their partners about their experiences when faced with the diagnosis of FGR.
Key stakeholders from 34 patient or disability organizations and medical stakeholders across Europe were interviewed. Two main topics emerged from the interviews: the problem of obtaining informed consent from the pregnant woman on whether or not to participate in the trial, and the psychological burden facing the woman making the decision when she has just been given the diagnosis of severe early-onset FGR. The former will be addressed in the design of the clinical trial; the latter was discussed in patient interviews.
Interviews in the EVERREST clinical sites with 24 women/couples with experience of a pregnancy complicated by severe early-onset FGR did not identify any fundamental ethical objections to the use of maternal VEGF growth factor gene therapy. Respondents had a generally favorable view of the ethical and social acceptability of EVERREST. Most pregnant women view their unborn child as a person early on in pregnancy and would generally “do anything to help this child.” While decision making in a pregnancy affected by severe early-onset FGR was difficult, women did not feel incapable of arriving at a decision regarding any treatment options but would listen to the advice of healthcare professionals and discuss the options with their partners. Women were also generally interested in participating in clinical trials particularly where the trial conferred a potential benefit to the unborn child.
The conclusions of the stakeholders and the former patients are broadly consistent and positive. Both empirical studies support the view that a trial would be useful and beneficial, provided that the consent considerations can be managed effectively. These conclusions were endorsed by the EVERREST Independent Ethics Advisory Committee.
Reproductive toxicology
Studies in two different human placental model systems have been used to investigate the effect of the EVERREST vector (Ad.VEGF-DΔNΔC) on placental function, gene transfer to the trophoblast, and vector cross-over to the fetal circulation: the in vitro human placental villous explant culture model and the ex vivo dual perfusion model of the human placenta. These human placental experimental data have demonstrated that, while the human placenta has a very low capacity to take up Ad.VEGF-DΔNΔC, access by the viral vector is very limited to the maternal-facing epithelium and transfer to the fetoplacental circulation is unlikely to occur. Optimization is completed of a quantitative polymerase chain reaction study to detect and quantify the presence of VEGF adenoviral vector on the fetal side of samples of human placental tissue perfusates from normal and FGR pregnancies. The quantification studies are being completed.
Clinical trial design
Development of the EVERREST Clinical Trial protocol has been a multinational and multidisciplinary exercise of fetal medicine, obstetric, neonatology, and interventional radiology experts from the EVERREST consortium. The Independent Ethics Advisory Committee, Data Safety Monitoring Board, and Trial Steering Committee have met and provided their input. Twenty women have been recruited to the prospective study cohort by clinical sites in the United Kingdom and Sweden (to end January 2015).
The EVERREST intervention was granted Orphan Medicinal Product Designation from the European Medicines Agency (number: EU/3/14/1415) in January 2015, and the consortium is seeking scientific advice on the clinical trial protocol from the European Medicines Agency.
Expected Outcome
The EVERREST clinical trial will aim to demonstrate the safety and tolerability of maternal uterine artery administration of VEGF in an adenoviral vector in women with pregnancies affected by severe early-onset FGR. In addition, it will aim to gain initial insights into the efficacy of the product. Together, these data will enable further development of the therapy through clinical trials to demonstrate efficacy, and will support regulatory approval and commercial launch. Our aspiration for this therapy, should we find that it is safe and effective, is for it to become the standard of care in the EU within the next 15–20 years.
The prospective study that is collecting data and samples from women who experience severe early-onset FGR will be the first database/biobank of its kind to concentrate on this condition from when women first have a diagnosis made. The study will be a rich source of data to explore both short- and long-term maternal and neonatal morbidities of this condition. It may also generate novel biomarkers that could be used to predict prognosis of severe early-onset FGR at the time of diagnosis.
