Principal Investigator: David Branch
Keywords: APS , SLE , Antiphospholipid Syndrome , Lupus , Pregnancy complications , Investigational drug , High risk Department: Maternal-Fetal Medicine
IRB Number: 00094818
Specialty: OB/Gyn, General, Maternal-Fetal Medicine, Maternal-Fetal Medicine
Sub Specialties: General Obstetrics, Recurrent Miscarriage,
Recruitment Status: Recruiting

Contact Information

Samantha Nielsen
sam.nielsen@hsc.utah.edu
801-585-7617

Brief Summary

We hypothesize that TNF-α blockade in pregnancy will significantly decrease the rate of fetal death and/or iatrogenic preterm birth due to preeclampsia or placental insufficiency in women with APS or SLE and LAC. In doing so, TNF-α blockade will result in a reduction in morbid and costly complications attributable to the iatrogenic preterm births in these challenging high-risk obstetric patients.

Outcomes: 

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), including fetal loss and preterm birth due to severe preeclampsia (PE) or placental insufficiency (PI). Diagnosis requires the appropriate clinical presentation and presence of serially positive tests for antiphospholipid antibodies (aPL), including lupus anticoagulant (LAC), IgG and/or IgM antibodies to cardiolipin (aCL) and IgG and IgM antibodies to β2 glycoprotein I (anti-β2-GP-I). 5-10% of women presenting with APOs may be diagnosed with APS. Therapy for individuals with APS focuses on preventing thrombosis, but thromboprophylaxis is only partially successful in averting poor pregnancy outcomes, and animal studies and histopathologic findings in placentas from women with APS emphasize that pro-inflammatory factors contribute to tissue injury.

In a prospective multicenter observational study (Predictors of pRegnancy Outcome: BioMarkers In antiphospholipid antibody Syndrome and Systemic Lupus Erythematosus, or PROMISSE), we assessed outcomes in 724 pregnant patients who received standard care. LAC was the primary clinical predictor of APOs after 12 wks gestation in women with aPL. In women with APS and LAC, 44% of pregnancies resulted in APOs. Among surviving fetuses that required delivery for PE or PI, the mean gestational age at delivery was 28 and 24 wks, respectively, despite nearly universal treatment with heparin and low dose aspirin. Considering only inpatient medical costs for the first year of life, the average cost for an infant born at these gestational ages is $86,000, and more than $200,000, respectively. Among survivors, the rate of neurodevelopmental delay and other disabilities is at least 15%. Thus, the long-term financial and medical burden to society is substantial, and the emotional cost to patient and family inestimable. Treatments designed to avoid these complications are critically needed. APOs associated with APS and LAC are due to a failure of adequate vascularization of the developing placenta, resulting in underperfusion of the intervillous space by oxygenated maternal blood and subsequent placental hypoxia. The clinical effects of placental hypoperfusion are PE and PI. Animal studies show that poor placental vascularization in APS is due primarily to inflammation. In a murine model of aPL-induced pregnancy complications, aPL target placental tissue and activate complement via the classical pathway, leading to the generation of potent anaphylatoxins, recruitment of neutrophils, release of proinflammatory mediators [tumor necrosis factor-alpha (TNF-α) and tissue factor] and anti-angiogenic factors (soluble fms-like tyrosine kinase 1, or sFlt-1), ultimately causing abnormal placentation and fetal death. Notably, in an aPL-induced mouse model of pregnancy complications and in antibody-independent models of PE, we found that TNF-α was a critical downstream effector of abnormal placental development, placental dysfunction, and fetal damage and that TNF-α blockade restored angiogenic balance and spiral artery remodeling and rescued pregnancies.

Based on our observations in PROMISSE and the favorable results of TNF-α blockade in our murine models, we hypothesize that TNF-α blockade in pregnancy will significantly decrease the rate of fetal death and/or preterm delivery due to PE or PI in women with APS and LAC. We expect that TNF-α blockade will result in a reduction in the devastating and costly complications attributable to preterm births in these challenging high-risk obstetric patients. With the clinical and biomarker risk stratification models and infrastructure created for PROMISSE, we are poised to conduct the first trial of a biologic therapy to prevent APOs in high-risk pregnancies in patients with APS.

Specific Aim 1: To determine whether TNF-α blockade added to a regimen of heparin and low dose aspirin during pregnancy reduces the rate of APOs in women with APS1 (prior vascular thrombosis and/or pregnancy morbidity) and LAC. We will conduct 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, on reducing the risk of APO in pregnant women with APS and LAC.

Specific Aim 2: To determine whether TNF-α blockade during pregnancy favorably alters angiogenic markers of poor placental vascularization in women with APS and LAC. Given that angiogenic dysregulation at 12-15 weeks gestation was highly predictive of APO in PROMISSE, angiogenic marker levels may provide an early measure of efficacy in this and future trials.

The potential public health impact of this trial extends beyond the population of women with APS. A reduction of severe APOs in certolizumab-treated patients would provide a rationale for trials of TNF-α blockade in pregnant women without APS, but at risk for severe PE or PI, and extend the benefits of measuring biomarkers in early pregnancy to many more patients.

Inclusion Criteria

Inclusion Criteria:

  1. Pregnant as defined by positive test for elevated ß-HCG and having a live, appropriate-size embryo by ultrasound, but < 8 weeks gestation;
  2. Antiphospholipid syndrome (APS);
  3. Positive for LAC on two or more occasions greater than 12 weeks apart one of which must be 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.  
  4. Age 18-40 (+364 days) years of age and able to give informed consent;
  5. 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

Exclusion Criteria:

  1. Hypertension (BP >140/90) present at screening;
  2. Multifetal gestation;
  3. Type 1 or type 2 diabetes antedating pregnancy;
  4. SLE patients requiring prednisone >10 mg/day;
  5. Platelet count <100,000 per microliter;
  6. Women currently taking prednisone greater than 10 mg daily for an autoimmune disorder, other than immune thrombocytopenia;
    1. More than 60 mg once daily in a tapering regimen or 20 mg once daily in a maintenance regimen for immune thrombocytopenia
  7. Women with urinary excretion with greater than 500 mg (0.5 g) per day (spot urine protein/creatinine ratio 0.5);
  8. Serum creatinine >1.2 mg/dL
  9. History of tuberculosis or untreated positive PPD;
  10. Women with a tuberculin skin test induration of 5 mm or greater; or positive quantiFERON-gold test
  11.  Women with HIV, Hepatitis B or Hepatitis C positive status;
  12. Known contraindications or relative contraindications to certolizumab
    1. Active infection, e.g., chronic hepatitis B.
    2. History of recurrent infection, e.g., recurrent cellulitis, or opportunistic infection.
    3. History of prior active/treated endemic mycoses in the last two years (including coccidiodomycosis, blastomycosis, or histoplasmosis).
    4. History of heart failure.
    5. History of peripheral demyelinating disease or Guillian-Barré syndrome.
    6. History of hematologic malignancy.
    7. Prior adverse reaction to certolizumab or other anti-TNF-α agent.

Note:  Conditions listed above as exclusionary diseases (TB, HIV, Hepatitis B, Hepatitis C) are tested as part of the standard of care prenatal assessments.  Results of these labs will be abstracted from the patients chart prior to determining if a patient is eligible for the study.  These assays are considered standard of care for this population and will not be conducted for research purposes only. 

APS patients who have started the study intervention prior to confirmation of two positive LAC results ≥12 weeks apart:  Twelve weeks after the initial positive LAC determination the LAC assay will be repeated.  If the result is negative, the patient, after consultation with her physician, will have the option of continuing the medication according to the established protocol.  

Patients who no longer test positive for LAC will not be included in the analysis of the clinical trial data.  However, these patients will continue to be monitored separately for outcomes, whether or not they choose to remain on the study treatment, and their data will be analyzed in a descriptive manner.