PROMISSE: Predictors of Pregnancy Outcome in Systemic Lupus Erythematosus (SLE) and Antiphospholipid Syndrome (APS)

Sponsor

Hospital for Special Surgery, New York (Other)

Overall Status

Recruiting

CT.gov ID

NCT00198068

Collaborator

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (NIH)

700

Enrollment

Locations

227

Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The PROMISSE Study is an observational study of 700 pregnant patients, enrolled at nine major clinical centers. The purpose of the study is 1) to determine whether certain proteins (called complement split products) that can injure healthy organs can be used to predict poor pregnancy outcome in patients with systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS), and/or 2) to determine whether elevated levels of circulating antiangiogenic factors predict pregnancy complications in patients with aPL antibodies and/or SLE.

Condition or Disease	Intervention/Treatment	Phase
Systemic Lupus Erythematosus Antiphospholipid Syndrome

Detailed Description

Thrombosis and pregnancy loss are common features of systemic lupus erythematosus (SLE), particularly in the presence of antiphospholipid (aPL) antibodies. The in vivo mechanisms by which aPL antibodies lead to vascular events and, specifically, to recurrent fetal loss are largely unknown. Studies in a mouse model of antiphospholipid antibody syndrome (APS) indicate that in vivo complement activation is necessary for fetal loss caused by aPL antibodies. This study represents an effort to translate these research observations on the potential role of complement activation in the pathogenesis of aPL antibody-mediated pregnancy loss to a clinically relevant human study.

In addition, studies in humans and mice have shown 1) that the balance of circulating angiogenic and antiangiogenic factors predicts preeclampsia and fetal growth restriction in healthy women, 2) circulating antiangiogenic factors cause endothelial dysfunction and abnormal placental development in animal models, and 3) complement activation leads to elevated levels of circulating antiangiogenic factors and complement inhibition prevents increased levels of antiangiogenic factors, placental dysfunction and fetal growth restriction in a mouse model of APS. This study will permit testing the hypothesis that, like in healthy women, the balance of circulating angiogenic and antiangiogenic factors predict complications in women with SLE and APS and to translate the findings in animal models into humans.

The PROMISSE Study is a prospective observational study that will follow 700 pregnant patients who will be grouped and analyzed according to the presence or absence of aPL antibodies and preexisting SLE. The patients are followed regularly during the course of the pregnancy, collecting medical and obstetrical information as well as serial blood specimens for complement and cytokine assays. The data obtained will be analyzed and used to identify mechanisms and predictors of poor fetal outcome. We expect that the insights provided through this study will suggest means to prevent, arrest or modify these conditions.

Study Design

Study Type:

Observational

Anticipated Enrollment :

700 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

Official Title:

Predictors of Pregnancy Outcome in Systemic Lupus Erythematosus (SLE) and Antiphospholipid Syndrome (APS)

Study Start Date :

Sep 1, 2003

Anticipated Primary Completion Date :

Aug 1, 2022

Anticipated Study Completion Date :

Aug 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Group 1: aPL+/SLE- Positive antiphospholipid antibodies (aPL) defined as positive LAC and/or anti cardiolipin IgG/IgM >= 40 units and/or anti-beta 2 glycoprotein I IgG or IgM >= 40 units; no SLE
Group 2: aPL+/SLE+ Positive antiphospholipid antibodies (aPL) defined as positive LAC and/or anti cardiolipin IgG/IgM >= 40 units and/or anti-beta 2 glycoprotein I IgG or IgM >= 40 units AND SLE defined as four or more American College of Rheumatology criteria for SLE.
Group 3: aPL-/SLE+ No antiphospholipid antibodies; SLE defined as four or more American College of Rheumatology criteria for SLE.
Group 4: aPL-/SLE- Healthy controls: no antiphospholipid antibodies; no SLE

Outcome Measures

Primary Outcome Measures

Otherwise unexplained fetal death occurring after 12 weeks gestation [End of pregnancy]
Fetal death occurring after 12 weeks' gestation and not explained by chromosomal abnormalities, anatomic malformations, or congenital infections.
Neonatal death [Time of neonatal death]
Neonatal death prior to hospital discharge and due to complications of prematurity
Preterm delivery prior to 36 weeks' gestation [End of pregnancy]
Indicated preterm delivery prior to 36 weeks' gestation because of gestational hypertension, preeclampsia-eclampsia or placental insufficiency
Small for gestational age (SGA) <5th %ile [End of pregnancy]
Small for gestational age (SGA) <5th %ile in the absence of anatomical or chromosomal abnormalities and/or delivery before 36 weeks because of intrauterine growth restriction (IUGR).

Secondary Outcome Measures

Gestational age [End of pregnancy]
Gestational age (weeks and days) at the end of pregnancy
Birth weight [End of pregnancy]
Birth weight
Number of days neonate requires positive pressure ventilation [Neonate discharge from hospital]
Number of days neonate requires positive pressure ventilation
Total number of days neonate is hospitalized [Neonate discharge from hospital]
Total number of days neonate is hospitalized

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Patient pregnant with live intrauterine pregnancy, as defined by positive test for elevated β-HCG, but ≤ 12 weeks by gestation (for subjects without aPL antibodies) and ≤18 weeks (for subjects with aPL antibodies)
Patient between the ages of 18-45 and able to give informed consent, or age < 18 years with parental consent
Hematocrit > 26%
For APL positive:
aCL: IgG >= 40 GPL units; IgM >= 40 MPL units
Positive LAC (RVVT, Kaolin, dilute TTI or PTT LA)
Anti-β2GPI: IgG >= 40 GPL units; IgM >= 40 MPL units
For control subjects:
At least one successful pregnancy
No history of fetal death (death of conceptus ≥ 10 weeks' gestation)
No more than 1 miscarriage < 10 weeks' gestation
No history of positive aPL in local lab or positive aPL in core labs at screening
Not currently a smoker
No medical problems requiring chronic treatment

Exclusion Criteria:

Diabetes mellitus (Type I and Type II) antedating pregnancy
Known or suspected hereditary complement deficiency (defined by CH50 = 0)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611
2	University of Chicago	Chicago	Illinois	United States	60637
3	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
4	NYU Langone Medical Center/Hospital for Joint Diseases	New York	New York	United States	10016
5	Hospital for Special Surgery	New York	New York	United States	10021
6	Columbia University Medical Center	New York	New York	United States	10032
7	Oklahoma Medical Research Foundation	Oklahoma City	Oklahoma	United States	73104
8	University of Utah Salt Lake City	Salt Lake City	Utah	United States	84132
9	Mt. Sinai Hospital	Toronto	Ontario	Canada	M5G 2K4
10	Guy's & St Thomas' NHS Foundation Trust	London		United Kingdom	SE1 7EH