Efficacy Study of Digibind for Treatment of Severe Preeclampsia

Pre-eclampsia Clinical Trial

Official title:

A Parallel, Double-blind, Placebo Controlled, Randomized Comparison of an Anti-digoxin Antibody (Digibind) Versus Placebo for the Treatment of Antepartum Patients With Severe Preeclampsia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00158743
• Other study ID #: DEEP
• Status: Completed
• Phase: Phase 2
• First received: September 8, 2005
• Last updated: July 17, 2014
• Start date: February 2004
• Est. completion date: December 2007

Study information

• Verified date: July 2014
• Source: BTG International Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 51
• Est. completion date: December 2007
• Est. primary completion date: December 2007
• Accepts healthy volunteers: No
• Gender: Female
• Age group: N/A and older

Eligibility

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

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Eclampsia
• Pre-Eclampsia

Intervention

Drug:
• Anti-digoxin antibody (FAB fragment)
intravenous administered, dose based on weight (assuming 4ng/mL EDLF concentration). Dose every 6 hours x 48 hours.

Other:
• sodium chloride

Locations

Country	Name	City	State
United States	Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 634, PO Box 250619	Charleston	South Carolina
United States	Department of OB-GYN, Division of Maternal Fetal Medicine, University of Texas Medical Branch, 301 University Boulevard	Galveston	Texas
United States	University of South Alabama	Mobile	Alabama
United States	Winnie Palmer Hospital	Orlando	Florida
United States	Phoenix Perinatal Associates	Phoenix	Arizona
United States	St Mark's Hospital	Salt Lake City	Utah
United States	Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center, PO Box 33932, 1501 Kings Highway	Shreveport	Louisiana
United States	St Mary's Health Center	St Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
BTG International Inc.	GlaxoSmithKline

Country where clinical trial is conducted

United States, 

References & Publications (8)

Adair CD, Buckalew V, Taylor K, Ernest JM, Frye AH, Evans C, Veille JC. Elevated endoxin-like factor complicating a multifetal second trimester pregnancy: treatment with digoxin-binding immunoglobulin. Am J Nephrol. 1996;16(6):529-31. — View Citation

Graves SW, Williams GH. An endogenous ouabain-like factor associated with hypertensive pregnant women. J Clin Endocrinol Metab. 1984 Dec;59(6):1070-4. — View Citation

Gruber KA, Whitaker JM, Buckalew VM Jr. Endogenous digitalis-like substance in plasma of volume-expanded dogs. Nature. 1980 Oct 23;287(5784):743-5. — View Citation

Gusdon JP Jr, Buckalew VM Jr, Hennessy JF. A digoxin-like immunoreactive substance in preeclampsia. Am J Obstet Gynecol. 1984 Sep 1;150(1):83-5. — View Citation

Krep H, Price DA, Soszynski P, Tao QF, Graves SW, Hollenberg NK. Volume sensitive hypertension and the digoxin-like factor. Reversal by a Fab directed against digoxin in DOCA-salt hypertensive rats. Am J Hypertens. 1995 Sep;8(9):921-7. — View Citation

Krep HH, Graves SW, Price DA, Lazarus M, Ensign A, Soszynski PA, Hollenberg NK. Reversal of sodium pump inhibitor induced vascular smooth muscle contraction with digibind. Stoichiometry and its implications. Am J Hypertens. 1996 Jan;9(1):39-46. — View Citation

Lopatin DA, Ailamazian EK, Dmitrieva RI, Shpen VM, Fedorova OV, Doris PA, Bagrov AY. Circulating bufodienolide and cardenolide sodium pump inhibitors in preeclampsia. J Hypertens. 1999 Aug;17(8):1179-87. — View Citation

Poston L, Morris JF, Wolfe CD, Hilton PJ. Serum digoxin-like substances in pregnancy-induced hypertension. Clin Sci (Lond). 1989 Aug;77(2):189-94. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Creatinine Clearance	change from baseline in creatinine clearance measured at 24 to 48 hours, comparing patients who received placebo with those who received digoxin immune fab	Baseline to 24-48 hours.	No