Efficacy Study of Digibind for Treatment of Severe Preeclampsia

• Proportion of patients during the treatment phase requiring: initiation of antihypertensive treatment;or
• in the case of patients entering the study already on an antihypertensive, requiring an increase in the dose or initiation of a secondary antihypertensive; or
• requiring delivery due to failure to control hypertension.
• Change in creatinine clearance from screening period.

• • requiring initiation of antihypertensive treatment, or
• • in the case of patients entering the study already on an antihypertensive, an increase in the dose or initiation of a secondary antihypertensive, or
• • requiring delivery due to failure to control hypertension;
• 2) Change in creatinine clearance from screening period.
• 1) Proportion of patients during the treatment phase

• Clinical Global Impressions (CGI) - Improvement* (see below)
• Responder analysis (Proportion of responders at the end of the treatment period. A responder is defined as a patient rated much or very much improved on the CGI-I scale.)
• Improvement scores across time.
• Change from baseline in Clinical Global Impressions - Severity score at time points of interest.
• Delivery latency from diagnosis and from first dose of study medication.
• Proportion of patients completing the 48-hour treatment phase.
• Change from baseline in: blood pressure,edema,renal and hepatic function parameters.
• Proportion of patients with hemolysis.
• Change from baseline in platelet count.
• Change from baseline in Doppler assessed blood flow in the fetal umbilical and middle cerebral arteries.
• Proportion of patients experiencing adverse events.
• *Clinical Global Impression-Improvement Scale
• SEVERITY
• Considering your total clinical experience with this
• patient population, how ill is the patient at this
• time? (Normal, not ill at all; Borderline ill; Mildly ill; Moderately ill; Markedly ill; Severely ill; Among the most extremely ill patients
• IMPROVEMENT
• Compared to her condition at admission to
• the study, how much has she changed? (Very much improved; Much improved; Minimally improved; No change; Minimally worse; Much worse; Very much worse)

• -Clinical Global Impressions (CGI) – Improvement* (see below)
• a. responder analysis (Proportion of responders at the end of the treatment period. A responder is defined as a patient rated much or very much improved on the CGI-I scale.)
• b. improvement scores across time
• -Change from baseline in Clinical Global Impressions – Severity score at time points of interest
• -Delivery latency from diagnosis and from first dose of study medication
• -Proportion of patients completing the 48-hour treatment phase
• -Change from baseline in: blood pressure,edema,renal and hepatic function parameters
• -Proportion of patients with hemolysis
• -Change from baseline in platelet count
• -Change from baseline in Doppler assessed blood flow in the fetal umbilical and middle cerebral arteries
• -Proportion of patients experiencing adverse events
• *Clinical Global Impression-Improvement Scale
• SEVERITY
• Considering your total clinical experience with this
• patient population, how ill is the patient at this
• time?
• 1. Normal, not ill at all
• 2. Borderline ill
• 3. Mildly ill
• 4. Moderately ill
• 5. Markedly ill
• 6. Severely ill
• 7. Among the most extremely ill patients
• IMPROVEMENT
• Compared to her condition at admission to
• the study, how much has she changed?
• 1. Very much improved
• 2. Much improved
• 3. Minimally improved
• 4. No change
• 5. Minimally worse
• 6. Much worse
• 7. Very much worse

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.

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.

• 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 Name: Digibind
• Drug: Digoxin Immune Fab ovine
  Dosing is a calculated amount based on weight of patient #vials = (4 x weight in kg)/(100) and assumption of EDLF concentration of 4 ng/mL
  Other Name: Digibind
• Drug: 0.9% sodium chloride
  normal saline placebo in equivalent volume to active comparator

• Active Comparator: 1
  Digibind treatment plus standard of care
  Interventions:

  • Drug: Anti-digoxin antibody (FAB fragment)
  • Drug: Digoxin Immune Fab ovine
• Placebo Comparator: 2
  0.9% sodium chloride placebo (intravenous)plus standard of care
  Intervention: Drug: 0.9% sodium chloride

• 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.
• 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.
• 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.
• Graves SW, Williams GH. An endogenous ouabain-like factor associated with hypertensive pregnant women. J Clin Endocrinol Metab. 1984 Dec;59(6):1070-4.
• 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.
• 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.
• 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.
• 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. No abstract available.

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 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