Background Pregnant women with antiphospholipid antibodies and/or lupus have higher rates of adverse pregnancy outcomes (APOs), such as fetal loss and preterm birth due to severe preeclampsia (PE) or placental insufficiency (PI). The presence of lupus anticoagulant (LAC) is the strongest predictor of an APO. At present, there is no effective treatment for women with these high-risk pregnancies, but in an animal model that mimics this human condition we found that TNF-α was a critical downstream effector of abnormal placental development and fetal damage, and that TNF-α blockade normalized placentation and spiral artery remodeling, and rescued pregnancies. We sought to determine whether TNF-α blockade during pregnancy, added to a regimen of heparin and low dose aspirin, reduces the rate of APOs in women with clinical APS and LAC.
Methods The IMPACT Study (IMProve Pregnancy in APS with Certolizumab Therapy) is an open label single-stage Phase II trial to evaluate the effect of certolizumab, a TNF-α inhibitor that does not cross the placenta and has been shown to be well tolerated in pregnancy, to reduce the risk of adverse outcomes in this population. Patients with APS and LAC are referred to IMPACT by their physicians (often before a planned pregnancy), consented and screened remotely by a study investigator, and medication is sent to the patient. They are treated with certolizumab from gestational week 8 through 28. Investigators contact patients every 2 weeks and receive medical reports and research blood samples monthly. Without the intervention being studied, 44% of these pregnancies were predicted to have serious complications, including severe pre-term preeclampsia, growth restricted fetuses, and/or fetal death. Assuming a target 50% reduction in APO rate with the intervention, forty-five evaluable pregnancies are required for 90% power to prove that the intervention reduces the rate of adverse outcomes.
Results Since May 2017, we have enrolled 33 patients from nine states. Characteristics: 61% had previous PE or PI <34 weeks requiring delivery, 70% had previous fetal death >10 weeks, 12% had neonatal death due to complications of prematurity; 42% venous thrombosis, 24% Stroke/TIA, 24% SLE. There have been no study drop-outs.
Conclusion We are successfully using a ‘rare disease study’ approach to conduct the first trial of a biologic therapy to prevent pregnancy complications women with APS and LAC. For rare conditions such as this, one must target assorted specialists (maternal-fetal medicine, hematology, rheumatology) for recruitment. Identifying patients preconceptionally is ideal, because improving placental vascularization requires enrollment early in pregnancy, and screening evaluations take time. Despite regulatory and logistic complexities and the small number of patients meeting inclusion criteria, their enthusiasm and that of their physicians has allowed us to move forward, albeit slowly.
Acknowledgements NIAMS, Lupus Research institute, Lupus Foundation of America.
Trial Registrations ClinicalTrials.gov NCT03152058.
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