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, 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. The primary outcome is a composite of two APOs associated with poor placentation: fetal death >10 WG or severe preeclampsia/placental insufficiency requiring delivery prior to 34 weeks gestation. The target sample size is 45 evaluable subjects. We hypothesize that the rate of the primary outcome in these pregnancies will be reduced from ~40% based on historical data to 20% with certolizumab.
Results Since May 2017 and despite the COVID-19 pandemic, we have enrolled 41 patients from ten states and 1 Canadian province. Characteristics: 56% previous PE or PI <34 weeks requiring delivery, 83% previous fetal death >10 weeks; 61% thrombosis and/or stroke and 24% SLE in addition to APS. During the trial, no new clinical manifestations of SLE have been observed in participants who did not carry the SLE diagnosis. There were no instances of new anti-DNA antibodies or increases in autoantibody titres in those patients who were anti-DNA antibody positive. ACL or anti-β2GPI antibody titres did not change during the trial. There have been no serious adverse events attributable to the study medication.
Conclusion We are successfully using a “rare disease study” approach to conduct the first trial of a biologic therapy to prevent pregnancy complications in women with APS and LAC. Certolizumab appears to be safe in this small trial. Certolizumab appears to be safe so far in this small trial. IMPACT must be completed before we can draw any conclusions about efficacy, and its results must be confirmed in a future study.
Acknowledgements NIAMS, Lupus Research institute, Lupus Foundation of America
ClinicalTrials. gov Identifier: NCT03152058
Lay Summary Pregnancies in patients with antiphospholipid syndrome who have a lupus anticoagulant in their blood have a high likelihood of ending in fetal death or very premature delivery because of poor placental development and preeclampsia. At present, there is no effective treatment for women with these high-risk pregnancies, but our work in an animal model that mimics this human condition shows that blockade of TNF-α, a pivotal mediator of inflammation, prevents adverse outcomes. Our study will determine whether treatment during pregnancy with certolizumab, a TNF-α inhibitor that does not cross the placenta, reduces the rate of poor pregnancy outcomes in women with clinical antiphospholipid syndrome; and, if successful, it will provide a new approach to protecting pregnancies in women with antiphospholipid syndrome and a rationale for trials of TNF-α blockade in women with other conditions, like SLE, who are at risk for preeclampsia or placental insufficiency.
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