IMPACT Study: IMProve Pregnancy in APS With Certolizumab Therapy

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.

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;

- APS and positive for LAC on two or more occasions greater than 12 weeks apart within
the previous 18 months and confirmed by review of medical records and core laboratory
testing;

a: The diagnosis of APS and LAC will be confirmed by one of the Co-PIs for each case
by a review of the medical records.

- Age 18-38 (+364 days) years of age and able to give informed consent

- Laboratory hematocrit >26% at time of screening.

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;

- 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:

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
coccidioidomycosis, blastomycosis, or histoplasmosis)

4. History of heart failure

5. History of peripheral demyelinating disease or Guillian-Barre syndrome

6. History of hematologic malignancy

7. Prior adverse reaction to certolizumab or o ther anti-TNF-α agent