IMPACT Study: IMProve Pregnancy in APS With Certolizumab Therapy

Study Overview
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Brief Summary
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This treatment trial evaluates the addition of an anti-tumor necrosis factor-alpha drug, certolizumab, to usual treatment (a heparin agent and low-dose aspirin) in pregnant women with antiphospholipid syndrome (APS) and repeatedly positive tests for lupus anticoagulant (LAC) to determine if this regimen will improve pregnancy outcomes. All enrolled patients will receive certolizumab, and pregnancy outcomes will be compared to those of women with APS and repeatedly positive tests for LAC enrolled in a previous study by the investigators.

Detailed Description
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Antiphospholipid syndrome (APS) is an autoimmune disorder that occurs most commonly in women of reproductive-age and is associated with thrombosis and adverse pregnancy outcomes (APOs), such as fetal loss and preterm birth due to severe preeclampsia (PE) or placental insufficiency (PI). Traditional therapy for APS during pregnancy has been a heparin agent and low dose aspirin. However, in PROMISSE, a prospective observational study of 724 patients, 44% of pregnancies in women with APS and LAC resulted in APOs despite treatment with heparin and low dose aspirin. The APOs in women with APS and LAC are due to failure of adequate vascularization of the developing placenta and subsequent inadequate blood flow to the placenta and fetus. Mouse models of APS show that poor placental vascularization in APS is a result of inflammation in the placenta. This inflammation leads to recruitment of neutrophils and release of more inflammatory mediators and anti-angiogenic factors. In the mouse model tumor necrosis factor-alpha is a critical downstream effector of abnormal placental development and fetal damage, and tumor necrosis factor-alpha blockade during pregnancy restores angiogenic balance, normalizes placental vascularization, and rescues pregnancies. Based on our observations in PROMISSE and the favorable results of tumor necrosis factor-alpha blockade in our mouse models, we hypothesize that tumor necrosis factor-alpha blockade will significantly decrease the rate of fetal death and preterm delivery due to PE and PI in women with APS and LAC. The study investigators aim to determine whether tumor necrosis factor-alpha blockade during pregnancy, added to a regimen of heparin and low dose aspirin, (1) reduces the rate of APOs in women with clinical APS and LAC, and (2) alters angiogenic markers of poor placental vascularization. Investigators will conduct an open label trial of certolizumab (a tumor necrosis factor-alpha inhibitor that does not cross the placenta). The regimen of heparin and low dose aspiring is a standard of care treatment for this patient population and is not considered part of the research intervention.

Official Title
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Certolizumab to Prevent Pregnancy Complications in High-Risk Patients With APS or SLE - (IMPACT Study: IMProve Pregnancy in APS With Certolizumab Therapy)

Conditions
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High Risk Pregnancy, Pregnancy Complications, Antiphospholipid Syndrome in Pregnancy, Lupus Anticoagulant Disorder

Intervention / Treatment
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* Drug: Certolizumab Pegol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pregnant as defined by positive test for elevated ß-HCG and having a live, appropriate sized embryo by ultrasound, but <8 weeks gestation; Antiphospholipid syndrome (APS); Positive for LAC on two or more occasions greater than 12 weeks apart within the previous 18 months. If a candidate for the study is newly diagnosed (<12 weeks) with APS, meets clinical criteria for APS and has one positive LAC confirmed by review of the medical record, she may be consented and screened. At baseline, LAC will be measured at the study core lab and she will be enrolled if it is found to be positive. The LAC measurement will be repeated 12 weeks after the initial determination and, if positive, she will remain in the study. Age 18-40 (+364 days) years of age and able to give informed consent Laboratory hematocrit >26% at time of screening. the diagnosis of APS and LAC will be confirmed by one of the Co-PI's for each case by a review of the medical records. Exclusion Criteria: Hypertension (BP >140/90) present at screening; Multifetal gestation; Type 1 or Type 2 diabetes antedating pregnancy; SLE patients requiring prednisone >10 mg/day; Platelet count <100,000 per microliter; Women currently taking prednisone greater than 10 mg daily for an autoimmune disorder, other than immune thrombocytopenia; a. More than 60 mg once daily in a tapering regimen or 20 mg once daily in a maintenance regimen for immune thrombocytopenia Women with urinary excretion with greater than 500 mg (0.5 g) per day (spot urine protein/creatinine ration 0.5); Serum creatinine >1.2 mg/dL History of tuberculosis or untreated positive PPD; Women with a tuberculin skin test induration of 5 mm or greater; or positive quantiFERON-gold test Women with HIV, Hepatitis B or Hepatitis C positive status; Known contraindications or relative contraindications to certolizumab: Active infection, e.g., chronic hepatitis B History of recurrent infection, e.g., recurrent cellulitis, or opportunistic infection History of prior active/treated endemic mycoses in the last two years (including coccidioidomycosis, blastomycosis, or histoplasmosis) History of heart failure History of peripheral demyelinating disease or Guillian-Barre syndrome History of hematologic malignancy Prior adverse reaction to certolizumab or o ther anti-TNF-α agent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Certolizumab Pegol<br>All participants are administered certolizumab [400 mg (given as two subcutaneous injections of 200mg) initially and 2 and 4 weeks later, followed by 200 mg every other week thereafter. 1st dose of certolizumab will be administered by 8 weeks and 6 days gestation and discontinued at 27 weeks 6 days. The regimen of heparin and low dose aspirin is a standard of care treatment for this patient population and is not considered part of the research intervention. | Drug: Certolizumab Pegol<br>* Certolizumab [400 mg (given as two subcutaneous injections of 200mg) initially and 2 and 4 weeks later, followed by 200 mg every other week thereafter] The 1st dose of certolizumab will be administered by 8 weeks and 6 days gestation and discontinued at 27 weeks 6 days. The regimen of heparin and low dose aspirin is a standard of care treatment for this patient population and is not considered part of the research intervention.<br>* Other names: Cimzia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fetal death and/or preterm delivery (<34 weeks) due to PE or PI in women with APS and LAC | Either of the following will constitute a primary outcome: Fetal death (>10 wks gestation) Severe preeclampsia or placental insufficiency requiring delivery prior to 34 weeks gestation. | 8 weeks gestation through 6-weeks postpartum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Additional adverse outcomes or pertinent concerns, possibly related to study intervention | Any one of the following is considered a secondary outcome: Neonatal death due to complications of prematurity because of preterm delivery for PE or PI Preterm labor or preterm rupture of membranes resulting in delivery prior to 36 weeks gestation PE or PI not requiring delivery prior to 34 weeks gestation Gestational age at delivery Maternal thrombosis Small-for-gestational age birthweight (<10th percentile) Known adverse reactions to certolizumab. | 8 weeks gestation through 6-weeks postpartum |