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IMPACT Study: IMProve Pregnancy in APS With Certolizumab Therapy

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ClinicalTrials.gov Identifier: NCT03152058
Recruitment Status : Recruiting
First Posted : May 12, 2017
Last Update Posted : March 13, 2019
Sponsor:
Collaborators:
Hospital for Special Surgery, New York
University of Toronto
NYU Langone Health
Information provided by (Responsible Party):
Ware Branch, University of Utah

Brief Summary:
This treatment trial evaluates the addition of an anti-tumor necrosis factor-alpha drug, certolizumab, to usual treatment (a heparin agent and low-dose aspirin) in pregnant women with antiphospholipid syndrome (APS) and repeatedly positive tests for lupus anticoagulant (LAC) to determine if this regimen will improve pregnancy outcomes. All enrolled patients will receive certolizumab, and pregnancy outcomes will be compared to those of women with APS and repeatedly positive tests for LAC enrolled in a previous study by the investigators.

Condition or disease Intervention/treatment Phase
High Risk Pregnancy Pregnancy Complications Antiphospholipid Syndrome in Pregnancy Lupus Anticoagulant Disorder Drug: Certolizumab Pegol Phase 2

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Certolizumab to Prevent Pregnancy Complications in High-Risk Patients With APS or SLE - (IMPACT Study: IMProve Pregnancy in APS With Certolizumab Therapy)
Actual Study Start Date : May 17, 2017
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : May 2021


Arm Intervention/treatment
Experimental: Certolizumab Pegol

All participants are administered certolizumab [400 mg (given as two subcutaneous injections of 200mg) initially and 2 and 4 weeks later, followed by 200 mg every other week thereafter.

1st dose of certolizumab will be administered by 8 weeks and 6 days gestation and discontinued at 27 weeks 6 days.

The regimen of heparin and low dose aspirin is a standard of care treatment for this patient population and is not considered part of the research intervention.

Drug: Certolizumab Pegol

Certolizumab [400 mg (given as two subcutaneous injections of 200mg) initially and 2 and 4 weeks later, followed by 200 mg every other week thereafter] The 1st dose of certolizumab will be administered by 8 weeks and 6 days gestation and discontinued at 27 weeks 6 days.

The regimen of heparin and low dose aspirin is a standard of care treatment for this patient population and is not considered part of the research intervention.

Other Name: Cimzia




Primary Outcome Measures :
  1. Fetal death and/or preterm delivery (<34 weeks) due to PE or PI in women with APS and LAC [ Time Frame: 8 weeks gestation through 6-weeks postpartum ]

    Either of the following will constitute a primary outcome:

    1. Fetal death (>10 wks gestation)
    2. Severe preeclampsia or placental insufficiency requiring delivery prior to 34 weeks gestation.


Secondary Outcome Measures :
  1. Additional adverse outcomes or pertinent concerns, possibly related to study intervention [ Time Frame: 8 weeks gestation through 6-weeks postpartum ]

    Any one of the following is considered a secondary outcome:

    1. Neonatal death due to complications of prematurity because of preterm delivery for PE or PI
    2. Preterm labor or preterm rupture of membranes resulting in delivery prior to 36 weeks gestation
    3. PE or PI not requiring delivery prior to 34 weeks gestation
    4. Gestational age at delivery
    5. Maternal thrombosis
    6. Small-for-gestational age birthweight (<10th percentile)
    7. Known adverse reactions to certolizumab.



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Ages Eligible for Study:   18 Years to 38 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Eligibility includes only pregnant women
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03152058


Contacts
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Contact: Kathryn Szczotka 801-581-7038 kathryn.szczotka@hsc.utah.edu
Contact: Marie Gibson 801-213-2845 marie.gibson@hsc.utah.edu

Locations
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United States, New York
Hospital for Special Surgery Recruiting
New York, New York, United States, 10021
Contact: Marta Guerra, MS    212-774-7361    guerram@hss.edu   
Principal Investigator: Jane Salmon, MD         
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84132
Contact: Marie K Gibson    801-213-2845    marie.gibson@hsc.utah.edu   
Contact: Kathryn Szczotka    801-581-7038    kathryn.szczotka@hsc.utah.edu   
Principal Investigator: D. Ware Branch, MD         
Canada, Ontario
TRIO Advancing Reproductive Care Not yet recruiting
Toronto, Ontario, Canada, M5G 2K4
Contact: Karen Spitzer, MSc    416-506-9203    kspitzer@triofertility.com   
Principal Investigator: Carl Laskin, MD         
Sponsors and Collaborators
Ware Branch
Hospital for Special Surgery, New York
University of Toronto
NYU Langone Health
Investigators
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Principal Investigator: D. Ware Branch, MD University of Utah

Publications:

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Responsible Party: Ware Branch, MD, University of Utah
ClinicalTrials.gov Identifier: NCT03152058     History of Changes
Other Study ID Numbers: 94818
First Posted: May 12, 2017    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Pregnancy Complications
Antiphospholipid Syndrome
Autoimmune Diseases
Immune System Diseases
Certolizumab Pegol
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents