Efficacy Study of Digibind for Treatment of Severe Preeclampsia

Phase 2

Completed

• Conditions: Pre-eclampsia
• Interventions: Other: sodium chloride; Drug: Anti-digoxin antibody (FAB fragment)

• Registration Number: NCT00158743
• Lead Sponsor: BTG International Inc.

Brief Summary

The purpose of this study is to determine whether a commercially available anti-digoxin antibody, Digibind, can delay delivery in patients with severe pre-eclampsia. If so, this would allow more time for maternally administered steroids to prevent the development of respiratory complications in premature infants.

Detailed Description

Preeclampsia (PE) is a serious complication of third trimester pregnancy manifested by high blood pressure, proteinuria, edema, encephalopathy sometimes with seizures, and hepatic failure. There is no known specific treatment, although palliative measures such as antihypertensive drugs, magnesium, steroids and early delivery improve outcomes. Multiple abnormalities have been demonstrated in PE but the relation of these abnormalities to the cause, pathophysiology and treatment is unknown. One of these abnormalities is elevation in the circulating level of a "digoxin-like" factor (EDLF), an unknown substance that cross reacts with digoxin antibodies and inhibits Na,K ATPase. An extensive literature supports the hypothesis that increased levels of EDLF may be a causative factor in the pathogenesis of hypertension. Increased levels of this factor are found both in maternal and fetal blood, both in normal pregnancy, and in pregnancy complicated by PE. Levels of this factor are higher in PE than in normal pregnancy suggesting it might play a role in the pathophysiology of PE.

Digibind (Glaxo Smith Kline) is a commercially available FAB fragment, antidigoxin antibody approved for the treatment of digoxin intoxication. In experimental models of hypertension with elevated EDLF levels, Digibind has been shown to lower blood pressure, suggesting that the antibody cross reacts with EDLF. These observations have led to the hypothesis that Digibind might ameliorate some of the manifestations of PE, especially the hypertension. Based on an extensive pre-clinical literature supporting that hypothesis, and encouraging results in 8 cases, a clinical trial is planned to test the effect of Digibind in severe PE. The study is a multi- site, parallel, double blind, placebo controlled, randomized trial. After randomization, 50 patients will be given the usual treatment for severe PE, plus study drug (Digibind or placebo) every six hours, for 48 hours. The study may be terminated during the treatment period for standard indications for early delivery.

Data collection will include: delivery latency, maternal blood pressure, antihypertensive use, renal function, hepatic function, CBC and platelet count, and umbilical artery blood flow by color doppler. Standard maternal and fetal monitoring will be followed. Newborn assessment will include: status at birth, APGAR score, NICU length of stay, respirator use and duration, and any medical complications. Adverse events will be recorded.

Study Timeline

• Study Start: 2004-02
• Study First Submitted: 2005-09-08
• Study First Submitted QC: 2005-09-08
• Study First Posted: 2005-09-12
• Primary Completion: 2007-12
• Study Completion: 2007-12
• Status Verified: 2014-07
• Results First Submitted: 2014-07-17
• Results First Submitted QC: 2014-07-17
• Last Update Submitted: 2014-07-17
• Results First Posted: 2014-08-08
• Last Update Posted: 2014-08-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 51

Inclusion Criteria

• A subject with a diagnosis of severe preeclampsia will be eligible for inclusion if she meets the following criteria:

  1. In the opinion of the investigator delivery is considered to be probably required within a 72 hour time period and, therefore, corticosteroid administration is needed.

  2. Meets both American College of Obstetricians (ACOG) criteria for preeclampsia (modified to limit selection to patients with the required severity)

     • A systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher occurring after 20 weeks of gestation in a woman whose blood pressure has previously been normal;
     • Proteinuria, with excretion of 0.3 g or more of protein in a 24-hour urine specimen or a urine dipstick reading of 1+ or more.

  3. Meets at least one of the following ACOG criteria for severe preeclampsia (modified to limit selection to patients with the required severity)

     . Proteinuria of 5 grams or higher in a 24-hour specimen or 3+ or greater on 2 random urine samples collected at least 4 hours apart

     • A systolic blood pressure of 160 mm Hg or higher or a diastolic blood pressure of 110 mm Hg or higher on two occasions six or more hours apart in a pregnant woman who is on bed rest;
     • Oliguria, with excretion of less than 500 ml of urine in 24 hours or average of ≤ 25 ml/hour over a 3 hour period;
     • Pulmonary edema;
     • Impairment of liver function [AST(SGOT) > 72 U/L or ALT(SGPT) > 72 U/L or LDH > 600 U/L or Total Bilirubin >1.2 mg/DL)];
     • Visual or cerebral disturbances;
     • Decreased platelet count (≥50,000/mm3 and ≤ 100,000/mm3).

  4. Has a fetal gestational age of 23 5/7 to 34 weeks.

Exclusion Criteria

1. Is in need of immediate delivery as soon as clinically appropriate
2. Eclampsia
3. Significant antecedent obstetrical problems which may interfere with study assessments or safe participation in the study
4. Evidence of non-reassuring fetal well being
5. Evidence of lethal fetal anomaly
6. Antecedent hypertension (hypertension secondary to preeclampsia, treated or untreated is allowed)
7. Antecedent renal, hepatic, or autoimmune disease
8. Medical or psychiatric disorder which is unstable or which might interfere with study assessments or safe participation in the study
9. Evidence on medical history/evaluation of use of or need for digitalis-like products currently or in the future
10. History of a severe allergic reaction to previous medication, severe asthma, or atopy. (Patients with a history of allergic reactions to antibiotics, papain, chymopapain, or other papaya extracts may be more susceptible to allergic reactions to Digibind®)
11. Prior use of antibodies/FAB fragments from sheep (e.g. Digibind®, DigiFab, CroFab)
12. Serum creatinine ≥ 1.5 mg/dl
13. Platelet count <50,000/mm3
14. Patient intends to breast feed and does not agree to wait for a minimum of seven days after the last Digibind® dose (a breast pump would be used for this seven day period)
15. Inability to understand and provide informed consent

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
placebo (sodium chloride)	sodium chloride	-
Digoxin immune fab	Anti-digoxin antibody (FAB fragment)	Digibind treatment plus standard of care

Primary Outcome Measures

Name	Time	Method
Change in Creatinine Clearance	Baseline to 24-48 hours.	change from baseline in creatinine clearance measured at 24 to 48 hours, comparing patients who received placebo with those who received digoxin immune fab

Trial Locations

Locations (8)

University of South Alabama; 🇺🇸 Mobile, Alabama, United States

Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center, PO Box 33932, 1501 Kings Highway; 🇺🇸 Shreveport, Louisiana, United States

Department of OB-GYN, Division of Maternal Fetal Medicine, University of Texas Medical Branch, 301 University Boulevard; 🇺🇸 Galveston, Texas, United States

St Mary's Health Center; 🇺🇸 St Louis, Missouri, United States

Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 634, PO Box 250619; 🇺🇸 Charleston, South Carolina, United States

Winnie Palmer Hospital; 🇺🇸 Orlando, Florida, United States

St Mark's Hospital; 🇺🇸 Salt Lake City, Utah, United States

Phoenix Perinatal Associates; 🇺🇸 Phoenix, Arizona, United States