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IMPACT Study: IMProve Pregnancy in APS With Certolizumab Therapy

Primary Purpose

High Risk Pregnancy, Pregnancy Complications, Antiphospholipid Syndrome in Pregnancy

Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Certolizumab Pegol
Sponsored by
David Ware Branch
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for High Risk Pregnancy

Eligibility Criteria

18 Years - 40 Years (Adult)FemaleDoes not accept healthy volunteers

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;
  • Antiphospholipid syndrome (APS);
  • Positive for LAC on two or more occasions greater than 12 weeks apart within the previous 18 months. If a candidate for the study is newly diagnosed (<12 weeks) with APS, meets clinical criteria for APS and has one positive LAC confirmed by review of the medical record, she may be consented and screened. At baseline, LAC will be measured at the study core lab and she will be enrolled if it is found to be positive. The LAC measurement will be repeated 12 weeks after the initial determination and, if positive, she will remain in the study.
  • Age 18-40 (+364 days) years of age and able to give informed consent
  • Laboratory hematocrit >26% at time of screening.

the diagnosis of APS and LAC will be confirmed by one of the Co-PI's for each case by a review of the medical records.

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 for an autoimmune disorder, other than immune thrombocytopenia;

    a. More than 60 mg once daily in a tapering regimen or 20 mg once daily in a maintenance regimen for immune thrombocytopenia

  • 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

Sites / Locations

  • Hospital for Special SurgeryRecruiting
  • University of UtahRecruiting
  • TRIO Advancing Reproductive CareRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Certolizumab Pegol

Arm Description

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.

Outcomes

Primary Outcome Measures

Fetal death and/or preterm delivery (<34 weeks) due to PE or PI in women with APS and LAC
Either of the following will constitute a primary outcome: Fetal death (>10 wks gestation) Severe preeclampsia or placental insufficiency requiring delivery prior to 34 weeks gestation.

Secondary Outcome Measures

Additional adverse outcomes or pertinent concerns, possibly related to study intervention
Any one of the following is considered a secondary outcome: Neonatal death due to complications of prematurity because of preterm delivery for PE or PI Preterm labor or preterm rupture of membranes resulting in delivery prior to 36 weeks gestation PE or PI not requiring delivery prior to 34 weeks gestation Gestational age at delivery Maternal thrombosis Small-for-gestational age birthweight (<10th percentile) Known adverse reactions to certolizumab.

Full Information

First Posted
May 1, 2017
Last Updated
October 17, 2023
Sponsor
David Ware Branch
Collaborators
Hospital for Special Surgery, New York, University of Toronto, NYU Langone Health
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1. Study Identification

Unique Protocol Identification Number
NCT03152058
Brief Title
IMPACT Study: IMProve Pregnancy in APS With Certolizumab Therapy
Official Title
Certolizumab to Prevent Pregnancy Complications in High-Risk Patients With APS or SLE - (IMPACT Study: IMProve Pregnancy in APS With Certolizumab Therapy)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 17, 2017 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
David Ware Branch
Collaborators
Hospital for Special Surgery, New York, University of Toronto, NYU Langone Health

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
High Risk Pregnancy, Pregnancy Complications, Antiphospholipid Syndrome in Pregnancy, Lupus Anticoagulant Disorder

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
55 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Certolizumab Pegol
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Certolizumab Pegol
Other Intervention Name(s)
Cimzia
Intervention Description
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.
Primary Outcome Measure Information:
Title
Fetal death and/or preterm delivery (<34 weeks) due to PE or PI in women with APS and LAC
Description
Either of the following will constitute a primary outcome: Fetal death (>10 wks gestation) Severe preeclampsia or placental insufficiency requiring delivery prior to 34 weeks gestation.
Time Frame
8 weeks gestation through 6-weeks postpartum
Secondary Outcome Measure Information:
Title
Additional adverse outcomes or pertinent concerns, possibly related to study intervention
Description
Any one of the following is considered a secondary outcome: Neonatal death due to complications of prematurity because of preterm delivery for PE or PI Preterm labor or preterm rupture of membranes resulting in delivery prior to 36 weeks gestation PE or PI not requiring delivery prior to 34 weeks gestation Gestational age at delivery Maternal thrombosis Small-for-gestational age birthweight (<10th percentile) Known adverse reactions to certolizumab.
Time Frame
8 weeks gestation through 6-weeks postpartum

10. Eligibility

Sex
Female
Gender Based
Yes
Gender Eligibility Description
Eligibility includes only pregnant women
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility 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; Antiphospholipid syndrome (APS); Positive for LAC on two or more occasions greater than 12 weeks apart within the previous 18 months. If a candidate for the study is newly diagnosed (<12 weeks) with APS, meets clinical criteria for APS and has one positive LAC confirmed by review of the medical record, she may be consented and screened. At baseline, LAC will be measured at the study core lab and she will be enrolled if it is found to be positive. The LAC measurement will be repeated 12 weeks after the initial determination and, if positive, she will remain in the study. Age 18-40 (+364 days) years of age and able to give informed consent Laboratory hematocrit >26% at time of screening. the diagnosis of APS and LAC will be confirmed by one of the Co-PI's for each case by a review of the medical records. 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 for an autoimmune disorder, other than immune thrombocytopenia; a. More than 60 mg once daily in a tapering regimen or 20 mg once daily in a maintenance regimen for immune thrombocytopenia 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: Active infection, e.g., chronic hepatitis B History of recurrent infection, e.g., recurrent cellulitis, or opportunistic infection History of prior active/treated endemic mycoses in the last two years (including coccidioidomycosis, blastomycosis, or histoplasmosis) History of heart failure History of peripheral demyelinating disease or Guillian-Barre syndrome History of hematologic malignancy Prior adverse reaction to certolizumab or o ther anti-TNF-α agent
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Joseph Worden
Phone
801-585-7617
Email
joseph.worden@hsc.utah.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Elizabeth Turner
Phone
801-585-0591
Email
elizabeth.e.turner@hsc.utah.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
D. Ware Branch, MD
Organizational Affiliation
University of Utah
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital for Special Surgery
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marta Guerra, MS
Phone
212-774-7361
Email
guerram@hss.edu
First Name & Middle Initial & Last Name & Degree
Jane Salmon, MD
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Elizabeth K Turner
Phone
801-585-0591
Email
elizabeth.e.turner@hsc.utah.edu
First Name & Middle Initial & Last Name & Degree
Joseph worden
Phone
801-585-7617
Email
joseph.worden@hsc.utah.edu
First Name & Middle Initial & Last Name & Degree
D. Ware Branch, MD
Facility Name
TRIO Advancing Reproductive Care
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2K4
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Karen Spitzer, MSc
Phone
416-506-9203
Email
kspitzer@triofertility.com
First Name & Middle Initial & Last Name & Degree
Carl Laskin, MD

12. IPD Sharing Statement

Plan to Share IPD
No
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IMPACT Study: IMProve Pregnancy in APS With Certolizumab Therapy

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