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

NCT ID: NCT00198068

Last Updated: 2025-04-13

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Total Enrollment

700 participants

Study Classification

OBSERVATIONAL

Study Start Date

2003-09-30

Study Completion Date

2026-03-31

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Systemic Lupus Erythematosus Antiphospholipid Syndrome

Study Design

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Observational Model Type

CASE_CONTROL

Study Time Perspective

PROSPECTIVE

Study Groups

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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

No interventions assigned to this group

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.

No interventions assigned to this group

Group 3: aPL-/SLE+

No antiphospholipid antibodies; SLE defined as four or more American College of Rheumatology criteria for SLE.

No interventions assigned to this group

Group 4: aPL-/SLE-

Healthy controls: no antiphospholipid antibodies; no SLE

No interventions assigned to this group

Eligibility Criteria

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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)
Minimum Eligible Age

18 Years

Maximum Eligible Age

45 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

Yes

Sponsors

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

NIH

Sponsor Role collaborator

Hospital for Special Surgery, New York

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Jane E. Salmon, M.D.

Role: PRINCIPAL_INVESTIGATOR

Hospital for Special Surgery, New York

Locations

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Northwestern University

Chicago, Illinois, United States

Site Status COMPLETED

University of Chicago

Chicago, Illinois, United States

Site Status COMPLETED

Johns Hopkins Hospital

Baltimore, Maryland, United States

Site Status COMPLETED

NYU Langone Medical Center/Hospital for Joint Diseases

New York, New York, United States

Site Status RECRUITING

Hospital for Special Surgery

New York, New York, United States

Site Status RECRUITING

Columbia University Medical Center

New York, New York, United States

Site Status COMPLETED

Oklahoma Medical Research Foundation

Oklahoma City, Oklahoma, United States

Site Status COMPLETED

University of Utah Salt Lake City

Salt Lake City, Utah, United States

Site Status RECRUITING

Mt. Sinai Hospital

Toronto, Ontario, Canada

Site Status RECRUITING

Guy's & St Thomas' NHS Foundation Trust

London, , United Kingdom

Site Status COMPLETED

Countries

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United States Canada United Kingdom

Central Contacts

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Marta M. Guerra, MS

Role: CONTACT

212-774-7361

Facility Contacts

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Marta M Guerra, MS

Role: primary

212-774-7361

Marta M Guerra, MS

Role: primary

212-774-7361

Tyler R Cavin

Role: primary

801-585-7617

Karen Spitzer

Role: primary

416-506-9203

References

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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.

Reference Type BACKGROUND
PMID: 15489858 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 14660741 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 11805148 (View on PubMed)

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 patients with antiphospholipid antibodies. Arthritis Rheum. 2012 Jul;64(7):2311-8. doi: 10.1002/art.34402.

Reference Type BACKGROUND
PMID: 22275304 (View on PubMed)

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. 2015 Aug 4;163(3):153-63. doi: 10.7326/M14-2235.

Reference Type BACKGROUND
PMID: 26098843 (View on PubMed)

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 patients with lupus and antiphospholipid antibodies: results of the PROMISSE study. Am J Obstet Gynecol. 2016 Jan;214(1):108.e1-108.e14. doi: 10.1016/j.ajog.2015.09.066. Epub 2015 Sep 29.

Reference Type BACKGROUND
PMID: 26432463 (View on PubMed)

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 study results. Lupus Sci Med. 2016 Jan 12;3(1):e000131. doi: 10.1136/lupus-2015-000131. eCollection 2016.

Reference Type BACKGROUND
PMID: 26835148 (View on PubMed)

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. Arthritis Rheumatol. 2016 Aug;68(8):1964-9. doi: 10.1002/art.39668.

Reference Type BACKGROUND
PMID: 26990620 (View on PubMed)

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 Cohort of Pregnant Patients with Lupus. Clin J Am Soc Nephrol. 2017 Jun 7;12(6):940-946. doi: 10.2215/CJN.11431116. Epub 2017 Apr 11.

Reference Type BACKGROUND
PMID: 28400421 (View on PubMed)

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 erythematosus and/or antiphospholipid antibodies. Ann Rheum Dis. 2018 Apr;77(4):549-555. doi: 10.1136/annrheumdis-2017-212224. Epub 2018 Jan 25.

Reference Type BACKGROUND
PMID: 29371202 (View on PubMed)

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, Blankenship D, Turner J, Banchereau J, Salmon JE, Pascual V. Longitudinal profiling of human blood transcriptome in healthy and lupus pregnancy. J Exp Med. 2019 May 6;216(5):1154-1169. doi: 10.1084/jem.20190185. Epub 2019 Apr 8.

Reference Type BACKGROUND
PMID: 30962246 (View on PubMed)

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 Systemic Lupus Erythematosus. Arthritis Care Res (Hoboken). 2018 Feb;70(2):230-235. doi: 10.1002/acr.23263. Epub 2017 Dec 29.

Reference Type BACKGROUND
PMID: 28480528 (View on PubMed)

Davis-Porada J, Kim MY, Guerra MM, Laskin CA, Petri M, Lockshin MD, Sammaritano LR, Branch DW, Sawitzke A, Merrill JT, Buyon JP, Salmon JE. Low frequency of flares during pregnancy and post-partum in stable lupus patients. Arthritis Res Ther. 2020 Mar 19;22(1):52. doi: 10.1186/s13075-020-2139-9.

Reference Type DERIVED
PMID: 32188491 (View on PubMed)

Yelnik CM, Lambert M, Drumez E, Le Guern V, Bacri JL, Guerra MM, Laskin CA, Branch DW, Sammaritano LR, Morel N, Guettrot-Imbert G, Launay D, Hachulla E, Hatron PY, Salmon JE, Costedoat-Chalumeau N. Bleeding complications and antithrombotic treatment in 264 pregnancies in antiphospholipid syndrome. Lupus. 2018 Sep;27(10):1679-1686. doi: 10.1177/0961203318787032. Epub 2018 Jul 17.

Reference Type DERIVED
PMID: 30016929 (View on PubMed)

Andrade D, Kim M, Blanco LP, Karumanchi SA, Koo GC, Redecha P, Kirou K, Alvarez AM, Mulla MJ, Crow MK, Abrahams VM, Kaplan MJ, Salmon JE. Interferon-alpha and angiogenic dysregulation in pregnant lupus patients who develop preeclampsia. Arthritis Rheumatol. 2015 Apr;67(4):977-87. doi: 10.1002/art.39029.

Reference Type DERIVED
PMID: 25603823 (View on PubMed)

Michael D Lockshin, Cohn E, Aslam A, Buyon JP, Salmon JE. Sex ratios among children of lupus pregnancies. Arthritis Rheum. 2013 Jan;65(1):282. doi: 10.1002/art.37718. No abstract available.

Reference Type DERIVED
PMID: 23044629 (View on PubMed)

Salmon JE, Heuser C, Triebwasser M, Liszewski MK, Kavanagh D, Roumenina L, Branch DW, Goodship T, Fremeaux-Bacchi V, Atkinson JP. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 2011 Mar;8(3):e1001013. doi: 10.1371/journal.pmed.1001013. Epub 2011 Mar 22.

Reference Type DERIVED
PMID: 21445332 (View on PubMed)

Related Links

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http://www.hss.edu/clinical-trials.asp

Clinical Trials at Hospital for Special Surgery

http://www.hss.edu/conditions_promisse-largest-investigation-lupus-pregnancy-loss.asp

The PROMISSE Study: The Nation's Largest Ever Investigation of Pregnancy Loss in Lupus

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467516/

PROMISSE: progress in understanding pregnancy complications in patients with SLE

Other Identifiers

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R01AR049772

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2014-309

Identifier Type: -

Identifier Source: org_study_id

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