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

Systemic Lupus Erythematosus Clinical Trial

— PROMISSE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00198068
• Other study ID #: 2014-309
• Secondary ID: R01AR049772
• Status: Recruiting
• Start date: September 2003
• Est. completion date: March 2025

Study information

• Verified date: April 2024
• Source: Hospital for Special Surgery, New York
• Contact: Marta M. Guerra, MS
• Phone: 212-774-7361
• Email: guerram[@]hss.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 700
• Est. completion date: March 2025
• Est. primary completion date: March 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

• Patient pregnant with live intrauterine pregnancy, as defined by positive test for elevated ß-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-ß2GPI: 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)

Related Conditions & MeSH terms

• Antiphospholipid Syndrome
• Lupus Erythematosus, Systemic
• Syndrome
• Systemic Lupus Erythematosus

Locations

Country	Name	City	State
Canada	Mt. Sinai Hospital	Toronto	Ontario
United Kingdom	Guy's & St Thomas' NHS Foundation Trust	London
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	Columbia University Medical Center	New York	New York
United States	Hospital for Special Surgery	New York	New York
United States	NYU Langone Medical Center/Hospital for Joint Diseases	New York	New York
United States	Oklahoma Medical Research Foundation	Oklahoma City	Oklahoma
United States	University of Utah Salt Lake City	Salt Lake City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
Hospital for Special Surgery, New York	National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Countries where clinical trial is conducted

United States,  Canada,  United Kingdom, 

References & Publications (12)

Buyon JP, Kim MY, Guerra MM, Laskin CA, Petri M, Lockshin MD, Sammaritano L, Branch DW, Porter TF, Sawitzke A, Merrill JT, Stephenson MD, Cohn E, Garabet L, Salmon JE. Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort Study. Ann Intern Med — View Citation

Buyon JP, Kim MY, Guerra MM, Lu S, Reeves E, Petri M, Laskin CA, Lockshin MD, Sammaritano LR, Branch DW, Porter TF, Sawitzke A, Merrill JT, Stephenson MD, Cohn E, Salmon JE. Kidney Outcomes and Risk Factors for Nephritis (Flare/De Novo) in a Multiethnic C — View Citation

Girardi G, Berman J, Redecha P, Spruce L, Thurman JM, Kraus D, Hollmann TJ, Casali P, Caroll MC, Wetsel RA, Lambris JD, Holers VM, Salmon JE. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest. 2003 Dec;112(11):1644-54. doi: 10.1172/JCI18817. Erratum In: J Clin Invest. 2004 Feb;113(4):646. — View Citation

Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med. 2004 Nov;10(11):1222-6. doi: 10.1038/nm1121. Epub 2004 Oct 17. — View Citation

Holers VM, Girardi G, Mo L, Guthridge JM, Molina H, Pierangeli SS, Espinola R, Xiaowei LE, Mao D, Vialpando CG, Salmon JE. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med. 2002 Jan 21;195(2):211-20. doi: 10.1084/jem.200116116. — View Citation

Hong S, Banchereau R, Maslow BL, Guerra MM, Cardenas J, Baisch J, Branch DW, Porter TF, Sawitzke A, Laskin CA, Buyon JP, Merrill J, Sammaritano LR, Petri M, Gatewood E, Cepika AM, Ohouo M, Obermoser G, Anguiano E, Kim TW, Nulsen J, Nehar-Belaid D, Blanken — View Citation

Kaplowitz ET, Ferguson S, Guerra M, Laskin CA, Buyon JP, Petri M, Lockshin MD, Sammaritano LR, Branch DW, Merrill JT, Katz P, Salmon JE. Contribution of Socioeconomic Status to Racial/Ethnic Disparities in Adverse Pregnancy Outcomes Among Women With Syste — View Citation

Kim MY, Buyon JP, Guerra MM, Rana S, Zhang D, Laskin CA, Petri M, Lockshin MD, Sammaritano LR, Branch DW, Porter TF, Merrill JT, Stephenson MD, Gao Q, Karumanchi SA, Salmon JE. Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in pa — View Citation

Kim MY, Guerra MM, Kaplowitz E, Laskin CA, Petri M, Branch DW, Lockshin MD, Sammaritano LR, Merrill JT, Porter TF, Sawitzke A, Lynch AM, Buyon JP, Salmon JE. Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythema — View Citation

Lockshin MD, Kim M, Laskin CA, Guerra M, Branch DW, Merrill J, Petri M, Porter TF, Sammaritano L, Stephenson MD, Buyon J, Salmon JE. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patie — View Citation

Yelnik CM, Laskin CA, Porter TF, Branch DW, Buyon JP, Guerra MM, Lockshin MD, Petri M, Merrill JT, Sammaritano LR, Kim MY, Salmon JE. Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPL-positive patients: validation of PROMISSE — View Citation

Yelnik CM, Porter TF, Branch DW, Laskin CA, Merrill JT, Guerra MM, Lockshin MD, Buyon JP, Petri M, Sammaritano LR, Stephenson MD, Kim MY, Salmon JE. Brief Report: Changes in Antiphospholipid Antibody Titers During Pregnancy: Effects on Pregnancy Outcomes. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Otherwise unexplained fetal death occurring after 12 weeks gestation	Fetal death occurring after 12 weeks' gestation and not explained by chromosomal abnormalities, anatomic malformations, or congenital infections.	End of pregnancy
Primary	Neonatal death	Neonatal death prior to hospital discharge and due to complications of prematurity	Time of neonatal death
Primary	Preterm delivery prior to 36 weeks' gestation	Indicated preterm delivery prior to 36 weeks' gestation because of gestational hypertension, preeclampsia-eclampsia or placental insufficiency	End of pregnancy
Primary	Small for gestational age (SGA) <5th %ile	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).	End of pregnancy
Secondary	Gestational age	Gestational age (weeks and days) at the end of pregnancy	End of pregnancy
Secondary	Birth weight	Birth weight	End of pregnancy
Secondary	Number of days neonate requires positive pressure ventilation	Number of days neonate requires positive pressure ventilation	Neonate discharge from hospital
Secondary	Total number of days neonate is hospitalized	Total number of days neonate is hospitalized	Neonate discharge from hospital

External Links

•   Clinical Trials at Hospital for Special Surgery
•   Lupus Anticoagulant Affects Pregnancy Outcomes
•   Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies
•   Pregnancy Safe for 80% of Women with Lupus
•   PROMISSE: progress in understanding pregnancy complications in patients with SLE
•   Study Sheds Light on Pregnancy Complications and Overturns Common Belief
•   The PROMISSE Study: The Nation's Largest Ever Investigation of Pregnancy Loss in Lupus