Pre-eclampsiaPhase 2NCT00158743
Efficacy Study of Digibind for Treatment of Severe Preeclampsia
A Phase 2 study testing Anti-digoxin antibody (FAB fragment) and sodium chloride in people with Pre-eclampsia, run by BTG International Inc. at 8 sites in United States.
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. Read more about this study
- Who is it for?
- Any age, women only
- Conditions the study is for
- Pre-eclampsia
- What is being tested?
- Anti-digoxin antibody (FAB fragment) and sodium chloride
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 51 participants
- Where
- 8 sitesUnited States
- Study dates
- Feb 2004to Dec 2007
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- Women only
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- A subject with a diagnosis of severe preeclampsia will be eligible for inclusion if she meets the following criteria:
- 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.
- 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.
- Meets at least one of the following ACOG criteria for severe preeclampsia (modified to limit selection to patients with the required severity)
Show all 14Show fewer
- . 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).
- Has a fetal gestational age of 23 5/7 to 34 weeks.
Who cannot join
- Is in need of immediate delivery as soon as clinically appropriate
- Eclampsia
- Significant antecedent obstetrical problems which may interfere with study assessments or safe participation in the study
- Evidence of non-reassuring fetal well being
- Evidence of lethal fetal anomaly
- Antecedent hypertension (hypertension secondary to preeclampsia, treated or untreated is allowed)
Show all 15Show fewer
- Antecedent renal, hepatic, or autoimmune disease
- Medical or psychiatric disorder which is unstable or which might interfere with study assessments or safe participation in the study
- Evidence on medical history/evaluation of use of or need for digitalis-like products currently or in the future
- 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®)
- Prior use of antibodies/FAB fragments from sheep (e.g. Digibind®, DigiFab, CroFab)
- Serum creatinine ≥ 1.5 mg/dl
- Platelet count <50,000/mm3
- 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)
- Inability to understand and provide informed consent
Trial locations and contacts
8 sites in 1 country.
8 sites in 1 country
United States8 sites
Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 634, PO Box 250619
Charleston, South Carolina, 29425
Department of OB-GYN, Division of Maternal Fetal Medicine, University of Texas Medical Branch, 301 University Boulevard
Galveston, Texas, 77555-0587
University of South Alabama
Mobile, Alabama, 36604
Winnie Palmer Hospital
Orlando, Florida, 32806
Phoenix Perinatal Associates
Phoenix, Arizona, 85014
St Mark's Hospital
Salt Lake City, Utah, 84124
Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center, PO Box 33932, 1501 Kings Highway
Shreveport, Louisiana, 71130
St Mary's Health Center
St Louis, Missouri, 63117
About this study
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
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.
Read the 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.
- Conditions
- Pre-eclampsia
- Being tested
- Anti-digoxin antibody (FAB fragment), sodium chloride
- Keywords
- Pre-eclampsia, Hypertension, Endogenous digitalis-like factor, Anti-digoxin antibody, Digibind
- Medical subject headings
- Pre-Eclampsia, Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Anti-digoxin antibody (FAB fragment)Drug
Also called Digibind
intravenous administered, dose based on weight (assuming 4ng/mL EDLF concentration). Dose every 6 hours x 48 hours.
sodium chlorideOther
| Study group | Role | What they receive |
|---|---|---|
| Digoxin immune fab | Active comparator | Digibind treatment plus standard of care Receives: Drug: Anti-digoxin antibody (FAB fragment) |
| placebo (sodium chloride) | Placebo comparator | Not described Receives: Other: sodium chloride |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: Baseline to 24-48 hours.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Sep 2005 (estimated)
- Study startFeb 2004
- Primary completionDec 2007
- Study completionDec 2007
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Pre-eclampsiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 51 participants (actual)
Sponsor and investigators
- Lead sponsor
- BTG International Inc.
- Sponsor type
- University, hospital or other
- Collaborators
- GlaxoSmithKline
- Responsible party
- Sponsor
- Investigators
- Vardaman M Buckalew, MD, Study chair, Wake Forest University Health Sciences
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00158743
- Sponsor's protocol ID
- DEEP
- Status last verified
- Jul 2014
- First submitted
- 8 Sep 2005
- Last updated
- 8 Aug 2014
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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. doi: 10.1159/000169054.
PubMed 8955766Gusdon 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. doi: 10.1016/s0002-9378(84)80114-3.
PubMed 6540989Poston L, Morris JF, Wolfe CD, Hilton PJ. Serum digoxin-like substances in pregnancy-induced hypertension. Clin Sci (Lond). 1989 Aug;77(2):189-94. doi: 10.1042/cs0770189.
PubMed 2548800Graves SW, Williams GH. An endogenous ouabain-like factor associated with hypertensive pregnant women. J Clin Endocrinol Metab. 1984 Dec;59(6):1070-4. doi: 10.1210/jcem-59-6-1070.
PubMed 6092405Lopatin 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. doi: 10.1097/00004872-199917080-00018.
PubMed 10466474Krep 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. doi: 10.1016/0895-7061(95)00181-N.
PubMed 8541008Krep 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. doi: 10.1016/0895-7061(95)00260-x.
PubMed 8834705Gruber KA, Whitaker JM, Buckalew VM Jr. Endogenous digitalis-like substance in plasma of volume-expanded dogs. Nature. 1980 Oct 23;287(5784):743-5. doi: 10.1038/287743a0. No abstract available.
PubMed 6253813
Study at a glance
From the registry record, last updated by the sponsor on 8 Aug 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00158743
- Acronym / sponsor ID
- DEEP
- Conditions
- Pre-eclampsia
- Keywords
- Pre-eclampsia, Hypertension, Endogenous digitalis-like factor, Anti-digoxin antibody, Digibind
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 51 participants (actual)
- Lead sponsor
- BTG International Inc.University, hospital or other
- Collaborators
- GlaxoSmithKline
- Study start
- Feb 2004
- Primary completion
- Dec 2007 (actual)
- Study completion
- Dec 2007 (actual)
- First posted
- 12 Sep 2005 (estimated)
- Results
- Posted 8 Aug 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Digoxin immune fab | Active comparator | Drug: Anti-digoxin antibody (FAB fragment)Digibind treatment plus standard of care |
| placebo (sodium chloride) | Placebo comparator | Other: sodium chloride |
Who may qualify
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (14 listed)
- A subject with a diagnosis of severe preeclampsia will be eligible for inclusion if she meets the following criteria:
- . 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
Key exclusion criteria (15 listed)
- Is in need of immediate delivery as soon as clinically appropriate
- Eclampsia
- Significant antecedent obstetrical problems which may interfere with study assessments or safe participation in the study
- Evidence of non-reassuring fetal well being
- Evidence of lethal fetal anomaly
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Anti-digoxin antibody (FAB fragment)Also: Digibindintravenous administered, dose based on weight (assuming 4ng/mL EDLF concentration). Dose every 6 hours x 48 hours. | Drug | Digoxin immune fab |
| sodium chloride | Other | placebo (sodium chloride) |
Primary outcome
Change in Creatinine Clearance
Time frame: 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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Aug 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 8955766Adair 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. doi: 10.1159/000169054.
- Background: PubMed 6540989Gusdon 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. doi: 10.1016/s0002-9378(84)80114-3.
- Background: PubMed 2548800Poston L, Morris JF, Wolfe CD, Hilton PJ. Serum digoxin-like substances in pregnancy-induced hypertension. Clin Sci (Lond). 1989 Aug;77(2):189-94. doi: 10.1042/cs0770189.
- Background: PubMed 6092405Graves SW, Williams GH. An endogenous ouabain-like factor associated with hypertensive pregnant women. J Clin Endocrinol Metab. 1984 Dec;59(6):1070-4. doi: 10.1210/jcem-59-6-1070.
- Background: PubMed 10466474Lopatin 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. doi: 10.1097/00004872-199917080-00018.
- Background: PubMed 8541008Krep 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. doi: 10.1016/0895-7061(95)00181-N.
- Background: PubMed 8834705Krep 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. doi: 10.1016/0895-7061(95)00260-x.
- Background: PubMed 6253813Gruber KA, Whitaker JM, Buckalew VM Jr. Endogenous digitalis-like substance in plasma of volume-expanded dogs. Nature. 1980 Oct 23;287(5784):743-5. doi: 10.1038/287743a0. No abstract available.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Vardaman M Buckalew, MD study chair
Wake Forest University Health Sciences
8 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Anti-digoxin antibody (FAB fragment) and sodium chloride in people with Pre-eclampsia, run by BTG International Inc. at 8 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Aug 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 8 Aug 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Creatinine Clearance (time frame: Baseline to 24-48 hours.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00158743, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Aug 2014.