Labetalol Versus Magnesium Sulfate (MgSO4) for the Prevention of Eclampsia Trial

NCT00293735 | Withdrawn Phase 2 DMC

• 1 other identifier: H-28505
• Study Type: interventional
• Target: N/A
• Locations: 2 countries
• Sites: 2

Brief Summary

Eclampsia is a major cause of perinatal morbidity and mortality. The pathophysiology is not known but magnetic resonance imaging (MRI) and Doppler data suggest that overperfusion of the cerebral tissues is a major etiologic factor. Hypertensive encephalopathy from overperfusion, and vascular damage from excessive arterial pressure (cerebral barotrauma) are believed to lead to vasogenic and cytotoxic cerebral edema, with resultant neuronal anomalies, seizure activity and cerebral bleeding if left unchecked. Doppler data have shown that cerebral perfusion pressure (CPP) is abnormally increased in severe preeclampsia and that autoregulation of the middle cerebral artery is affected by this condition leading to increased CPP. Magnesium sulfate (MgSO4) is the most widely accepted eclampsia treatment and prophylactic agent, and it has been used in the USA since the 1950's. Despite widespread use, its mechanism of action is unknown. MgSO4 is given intravenously or intramuscularly and requires specialized nursing training and monitoring to minimize toxicity from respiratory and cardiac depression. Labetalol, a combined alpha and beta blocker, has been used for many years to safely treat hypertension in preeclamptic women, and is now known to reduce CPP in women with preeclampsia. In the United Kingdom labetalol was for many years used as the sole agent in treating preeclampsia, and the rate of seizure was no different to that reported in the USA with MgSO4. Since labetalol can be administered orally, is economical, has low toxicity potential, does not require specialized training to administer or monitor, and decreases CPP, it may be an ideal agent for controlling blood pressure (BP) and decreasing the incidence of eclampsia in women with preeclampsia. The current study is a multicenter, randomized, controlled trial to compare the anti-seizure effect of parenteral MgSO4 versus oral labetalol in hypertensive pregnant women who are eligible for MgSO4 therapy. The primary outcome measure is eclampsia, and the secondary outcome measures include blood pressure control, and relevant antenatal, intrapartum, and postnatal maternal and fetal/neonatal parameters including adverse effects and complications. Inclusion criteria are deliberately broad in order to make the study clinically relevant. Hypertensive pregnant women, in whom the decision for delivery has been made, will be enrolled after written, informed consent. Patients will be randomized to receive MgSO4 therapy as given in their institution, versus oral labetalol (200mg/q6 hours), from enrollment in the study until 24 hours post delivery. There will be 4000 patients in each arm of the study and analysis will be by intention-to-treat. The study is powered to show both therapeutic superiority as well as clinical equivalence. This study has the potential to change the way preeclampsia is managed, and will represent a major advance in terms of the availability and safety of prophylactic therapy, especially in developing nations where MgSO4 is underutilized due to cost constraints.

Conditions

Preeclampsia; Pregnancy Induced Hypertension; Gestational Hypertension; Chronic Hypertension; Superimposed Preeclampsia

Keywords

Preeclampsia; Pregnancy; Hypertension; Eclampsia; HELLP Syndrome; Seizures; Prevention

Outcome Measures

Primary Outcomes (1)

• Occurrence of eclamptic seizure(s) after enrollment in the study.

  24 Hours Postpartum

Secondary Outcomes (11)

• Maternal: Blood pressure, pulse pressure and heart rate changes

  24 hours postpartum

• Need for additional antihypertensive medication (defined by need to control BP > 160 mmHg systolic and/or 110 mmHg)

  24 hours postpartum

• Subjective assessment of side effects by the patient

  24 hours postpartum

• Objective assessment of new onset complications and/or side effects by the treating clinicians

  24 hours postpartum

• Labor and delivery parameters including; induction to delivery interval, rate of cervical dilatation, oxytocin dosages, length of labor, delivery route, blood loss at delivery, and postpartum course; and

  24 hours postpartum

Study Arms (2)

1. Labetolol

ACTIVE COMPARATOR

Drug: labetalol (seizure prevention)

2. Magnesium Sulfate

ACTIVE COMPARATOR

Drug: MgSO4 (seizure prevention)

Interventions

labetalol (seizure prevention) DRUG

20mg IV (can be increased to an escalating dose of maximum of 80 mg (20mg, 40 mg, 80 mg q 20min) Cumulative max of 240 mg. 20mg labetalol PO every 6 hours

1. Labetolol

MgSO4 (seizure prevention) DRUG

4-6g bolus over 20 minutes; 1-2 grams/hr Discontinued 24 hours after delivery.

2. Magnesium Sulfate

Eligibility Criteria

• Age: 15 Years - 60 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Any patient with preeclampsia (BP \> 140 systolic and/or \> 90 mmHg diastolic with 1+ or more proteinuria \[or a 24 hour specimen with \> 300 mg/day\]), chronic hypertension (or superimposed preeclampsia), or gestational hypertension deemed to be at risk for eclamptic convulsions and who would routinely be treated in the participating institution with some form of anti-seizure prophylaxis during labor and delivery.

You may not qualify if:

• Any patient for whom informed consent cannot be obtained.
• Any patient who has received an antihypertensive medication within 6 hours prior to enrollment will not be eligible but those who have received antihypertensive medications other than beta-blockers or magnesium sulfate may still be enrolled as long as they have not been given a dose within the 6 hours prior to enrollment. If a patient has received MgSO4 or a short acting beta-blocker or calcium channel blocker more than 12 hours prior to enrollment or if they have received a long acting beta-blocker more than 24 hours before enrollment she may still be considered eligible. This stipulation will allow increased recruitment of patients especially those with chronic hypertension and those transferred from outlying institutions. We expect these patients to be a minority of the enrollment.
• A history of bronchial asthma, emphysema, heart block, angina, cardiomyopathy or myocardial infarction.
• Any history or signs of congestive cardiac failure, or arrhythmia with a ventricular rate of less than 60 bpm.
• Patients with severe mental or physical disorders which, in the opinion of the investigators, might affect responsiveness to therapy or any other aspect of the study.
• Patients who are allergic to drugs with a chemical structure similar to labetalol or magnesium sulfate.
• Patients given magnesium sulfate, labetalol or short acting beta blockers or calcium channel blockers less than 12 hours prior to enrollment in the study.
• Evidence of fetal distress or fetal anomalies.
• Inability to secure intravenous access.
• Patient's primary physician declines to enroll patient in study.

Sponsors & Collaborators

• Baylor College of Medicine: lead

Study Sites (2)

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Institute of Maternal and Child Health Medicine

Kerala, 673008, India

Location

Related Publications (7)

• Belfort MA, Anthony J, Saade GR, Allen JC Jr; Nimodipine Study Group. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med. 2003 Jan 23;348(4):304-11. doi: 10.1056/NEJMoa021180.

  PMID: 12540643 BACKGROUND

• Belfort MA. Is high cerebral perfusion pressure and cerebral flow predictive of impending seizures in preeclampsia? A case report. Hypertens Pregnancy. 2005;24(1):59-63. doi: 10.1081/PRG-45776.

  PMID: 16036391 BACKGROUND

• Belfort MA, Tooke-Miller C, Allen JC Jr, Dizon-Townson D, Varner MA. Labetalol decreases cerebral perfusion pressure without negatively affecting cerebral blood flow in hypertensive gravidas. Hypertens Pregnancy. 2002;21(3):185-97. doi: 10.1081/PRG-120015845.

  PMID: 12517326 BACKGROUND

• Belfort MA, Tooke-Miller C, Varner M, Saade G, Grunewald C, Nisell H, Herd JA. Evaluation of a noninvasive transcranial Doppler and blood pressure-based method for the assessment of cerebral perfusion pressure in pregnant women. Hypertens Pregnancy. 2000;19(3):331-40. doi: 10.1081/prg-100101995.

  PMID: 11118407 BACKGROUND

• Riskin-Mashiah S, Belfort MA. Cerebrovascular hemodynamics in chronic hypertensive pregnant women who later develop superimposed preeclampsia. J Soc Gynecol Investig. 2005 Jan;12(1):28-32. doi: 10.1016/j.jsgi.2004.08.002.

  PMID: 15629667 BACKGROUND

• Belfort MA, Varner MW, Dizon-Townson DS, Grunewald C, Nisell H. Cerebral perfusion pressure, and not cerebral blood flow, may be the critical determinant of intracranial injury in preeclampsia: a new hypothesis. Am J Obstet Gynecol. 2002 Sep;187(3):626-34. doi: 10.1067/mob.2002.125241.

  PMID: 12237639 BACKGROUND

• Belfort MA, Saade GR, Yared M, Grunewald C, Herd JA, Varner MA, Nisell H. Change in estimated cerebral perfusion pressure after treatment with nimodipine or magnesium sulfate in patients with preeclampsia. Am J Obstet Gynecol. 1999 Aug;181(2):402-7. doi: 10.1016/s0002-9378(99)70569-7.

  PMID: 10454691 BACKGROUND

MeSH Terms

Conditions

Pre-Eclampsia; Hypertension, Pregnancy-Induced; Hypertension; Eclampsia; HELLP Syndrome; Seizures

Interventions

Labetalol

Condition Hierarchy (Ancestors)

Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Vascular Diseases; Cardiovascular Diseases; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Salicylamides; Amides; Amines

Study Officials

• Michael A Belfort, MD, PhD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chairman and Professor

Study Record Dates

• First Submitted: February 16, 2006
• First Posted: February 17, 2006
• Study Start: June 1, 2015
• Primary Completion: January 1, 2017
• Study Completion: January 1, 2017
• Last Updated: January 13, 2017

Record last verified: 2017-01

Locations

US (1); IN (1)