The Use of Eculizumab in HELLP Syndrome

Eculizumab in HELLP Syndrome

This research study is being performed to see if women diagnosed with early preterm Hemolysis, Elevated Liver Enzymes, Low Platelets (HELLP) syndrome (estimated gestational ages of 23-30 weeks) benefit from a medication called eculizumab (ECU). This drug blocks a part of the immune system called complement. By blocking this part of the immune system, eculizumab may stop or reverse the progression of the HELLP syndrome disease. The investigators will also look to see if this drug is effective and benefits both the mother and fetus.

Study Overview

• Status: Completed
• Conditions: Morbidity;Newborn; Preeclampsia Severe; Complement Abnormality; HELLP Syndrome (HELLP), Third Trimester; Maternal Injury
• Intervention / Treatment: Drug: Eculizumab

Detailed Description

Preeclampsia is a devastating multisystem disorder of pregnancy that manifests as hypertension with or without proteinuria and/or end organ damage caused by endothelial dysfunction and occurs in 3-5% of all pregnancies. Notably, preeclampsia accounts for 30% of all preterm deliveries, which results in neonatal intensive care unit admissions, increased health care cost, severe neonatal morbidity, and neonatal mortality. HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome is the most severe variant of this disorder, and affects approximately 0.1-0.2% of all pregnancies. Despite its prevalence, the cellular biology of HELLP syndrome is unclear resulting in supportive treatment regimens like fetal monitoring, steroids for fetal lung maturity, magnesium for seizure prophylaxis, management of hypertension and ultimately delivery that results in iatrogenic preterm birth.

Complement is an enzymatic cascade of approximately 50 proteins which are activated by the classic pathway of complement, the lectin pathway of complement, and the alternative pathway of complement (APC). While the classic pathway depends on antigen-antibody complexes (i.e., lupus) for activation, the APC is antibody independent and has various triggers including infection, trauma, and pregnancy.

The investigators' research lab created a novel functional assay, the modified Ham (mHam) assay, to diagnose highly morbid diseases of the APC such atypical hemolytic uremic syndrome (aHUS). Because of the phenotypic similarities of aHUS and HELLP syndrome the investigators' lab undertook a study to test women diagnosed with complete (classic) HELLP and partial (atypical) HELLP syndrome established by Tennessee and American College of Obstetrics and Gynecology (ACOG) criteria to observe if there was dysregulation and overactivation of the APC. The investigators found that most women with HELLP syndrome have APC upregulation; furthermore, it could be inhibited in vitro with anti-C5 monoclonal antibody. In addition, the investigators recently showed approximately 50% of women with HELLP syndrome have germline mutations associated with regulatory proteins of the APC 12. These are the same mutations associated with aHUS; further, 4 of the 5 women with germline mutations are positive by the mHam assay correlating genotype to phenotype. With the investigators' current data that HELLP syndrome is similar to aHUS, the investigators propose an open label clinical trial of ECU administration to women with HELLP syndrome at 23-30 weeks gestation.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Arthur J Vaught; Phone Number: 4048496018; Email: avaught2@jhmi.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The Johns Hopkins University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pregnant women diagnosed with HELLP syndrome less than 30 weeks gestation.

Exclusion Criteria:

Women with

• Disseminated intravascular coagulopathy
• Non-reassuring fetal status necessitating delivery
• Non-viable fetuses
• Stroke
• Fetal demise intra-utero
• Eclamptic seizure
• Known atypical hemolytic uremic syndrome
• Familial or acquired thrombocytopenia purpura
• Paroxysmal nocturnal hemoglobinuria
• Allergy to eculizumab will be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HELLP Syndrome at less than 30 weeks gestation; Women diagnosed with HELLP syndrome at 23-30 weeks gestation will receive eculizumab.	Drug: Eculizumab; Participants will receive eculizumab at diagnosis of HELLP syndrome. Participants will receive a maximum of 4 doses.; Other Names: Soliris

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in aspartate aminotransferase (AST) level	AST measured in units/L.	Baseline, 72 hours
Change in alanine aminotransferase (ALT)	ALT measured in IU/L.	Baseline, 72 hours
Change in lactate dehydrogenase levels (LDH)	LDH measured in units/L.	Baseline, 72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Latency of pregnancy	Latency of pregnancy measured in days after eculizumab administration	Up to 7 days
Maternal number of units of blood products transfused	Blood products (packed red blood cells, fresh frozen plasma, platelets, cryoprecipitate) measured in units.	Up to 7 days
Maternal postpartum length of stay	Postpartum length of stay, measured from delivery to time of discharge in days.	Up to 36 days

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Arthur J Vaught, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2021
• Primary Completion (Actual): August 31, 2023
• Study Completion (Actual): September 4, 2023

Study Registration Dates

• First Submitted: September 24, 2019
• First Submitted That Met QC Criteria: September 24, 2019
• First Posted (Actual): September 25, 2019

Study Record Updates

• Last Update Posted (Estimated): November 14, 2023
• Last Update Submitted That Met QC Criteria: November 13, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Pregnancy Complications; Hypertension, Pregnancy-Induced; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Syndrome; Pre-Eclampsia; HELLP Syndrome; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab
• Other Study ID Numbers: IRB00193549; 1K12HD085845-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No