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Rosuvastatin in Order to Induce Preeclampsia Resolution in Severe PET up to 48 Hours Following Delivery

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ClinicalTrials.gov Identifier: NCT02314286
Recruitment Status : Unknown
Verified December 2014 by Ofer Beharier, Soroka University Medical Center.
Recruitment status was:  Not yet recruiting
First Posted : December 11, 2014
Last Update Posted : December 11, 2014
Sponsor:
Information provided by (Responsible Party):
Ofer Beharier, Soroka University Medical Center

Tracking Information
First Submitted Date  ICMJE November 16, 2014
First Posted Date  ICMJE December 11, 2014
Last Update Posted Date December 11, 2014
Study Start Date  ICMJE December 2014
Estimated Primary Completion Date July 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 10, 2014)
To evaluate the effect of Rosuvastatin on the severe preeclampsia resolution at 48 hours after delivery [ Time Frame: 48 hours ]
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: December 10, 2014)
  • Time from delivery until reduction in general blood pressure [ Time Frame: 48 hours ]
    systolic pressure below 140mm\Hg or diastolic pressure below 90mm\Hg. Measurement will be carried out according to standard Protocol: before delivery, every 30 minutes during the first 2 hours post-delivery then every hour until discharge.
  • Duration and dosage of hypertensive treatment due to severe hypertension (systolic greater than 160 mmHg or diastolic greater than 110 mmHg [ Time Frame: 48 hours ]
  • Evaluation of renal function through urine Protein / creatinine ratio measurement will be examined before delivery and 6, 12, 18, 24 hours post-delivery. In addition the time from delivery to polyuria will be assessed via measuring urine output per hour. [ Time Frame: 48 hours ]
  • Rate of liver transminases resolution. Samples will be taken before delivery and every 6 hours post-delivery (part of the routine follow-up of preeclampsia). [ Time Frame: 48 hours ]
  • Examining time to thrombocytopenia resolution. Samples will be taken before delivery and every 6 hours post-delivery (part of the routine follow-up of preeclampsia). [ Time Frame: 48 hours ]
  • Length assessment of intensive care unit hospitalization [ Time Frame: 48 hours and beyond ]
  • Immunological assessment of the placenta [ Time Frame: 48 hours and beyond ]
    We intend to test the following metrics:
    1. The amount and activity of NK cells in the placenta.
    2. The rate of secretion of angiogenic factors VEGF, SFLT-1, PLGF and inflammation factors TGF-ALFA I and IL-6.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rosuvastatin in Order to Induce Preeclampsia Resolution in Severe PET up to 48 Hours Following Delivery
Official Title  ICMJE Rosuvastatin Use in Order to Induce Preeclampsia Resolution in Severe Preeclampsia Cases up to 48 Hours Following Delivery
Brief Summary Prospective randomized single blind trial. Study population are women diagnosed with severe pre-eclampsia during singleton pregnancy, between 24+0 weeks and 41+6 weeks gestational age. The purpose of the study is to evaluate the effect of Rosuvastatin on the severe preeclampsia resolution at 48 hours after delivery. After screening and signing an informed consent form, before entering delivery room, a randomization 1:1 will be carried. 50 women will be in the treatment arm while 50 will be in the control arm. Both groups will be treated according to ACOG (The American College of Obstetricians and Gynecologists has the following clinical guidelines related to deliveries before 39 weeks) guidelines. In addition, following randomization experimental group will be treated with Rosuvastatin 40mg that will be administrated orally with or without food. Treatment will be carried within the first hour following delivery. Another dose will be given 24 hours after first administration. Control group will be treated with placebo.
Detailed Description

Preeclampsia is a disorder of widespread vascular endothelial malfunction and vasospasm that occurs after 20 weeks' gestation and can present as late as 4-6 weeks' postpartum. It is clinically defined by as blood pressure ≥140 mmHg systolic and ≥90 mmHg diastolic diagnosed for the first time after 20 weeks' gestation together with >300mg proteinuria/24 hours.

The global incidence of preeclampsia has been estimated at 5-14% of all pregnancies. Pre-eclampsia affects approximately 6-8% of all pregnancies worldwide. Pre-eclampsia affects 3-5% of all first time pregnancies, but early severe pre-eclampsia occurs in only 1:200 pregnancies.

Significant risk factors for pre-eclampsia are as follows: Nulliparity, age >40 years, black race, family history, chronic renal disease, chronic hypertension, antiphospholipid syndrome, diabetes mellitus , multiple gestation and high body mass index.

Mild preeclampsia is defined as the presence of hypertension (BP ≥140/90 mm Hg) on 2 occasions, at least 6 hours apart, but without evidence of end-organ damage.

Severe preeclampsia is defined as the presence of 1 of the following symptoms or signs in the presence of preeclampsia:

marked elevation of blood pressure (>160/110 mmHg), severe proteinuria (>5 g/24 hours), or evidence of central nervous system (CNS) dysfunction (headaches, blurred vision, seizures, coma), renal dysfunction (oliguria or creatinine > 1.5 mg/dL), pulmonary edema, hepatocellular injury (ALT > 2-fold the upper limits of normal), hematologic dysfunction (platelet count < 100,000/L or DIC), or placental dysfunction (oligohydramnios or severe intrauterine growth restriction). The HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is a special subgroup of severe preeclampsia and is a major cause of morbidity and mortality.

Eclampsia is defined as seizures that cannot be attributable to other causes in a woman with preeclampsia.

The optimal management of a woman with preeclampsia depends on gestational age and disease severity Management of preeclampsia is challenging because it requires the clinician to balance the health of the mother and fetus simultaneously. Patients with mild preeclampsia are often induced after 37 weeks gestation. Before this, the immature fetus is treated with expectant management with bed rest, close monitoring of blood pressure and renal function, and careful fetal surveillance. For women with severe preeclampsia, induction of delivery should be considered after 34 weeks gestation unless the patient is eligible for expectant management in a tertiary hospital setting. The definitive treatment of preeclampsia is delivery of the fetus and placenta. Anti-hypertensive drugs are essential for severe hypertension (≥160 mmHg systolic or ≥110 mmHg diastolic) for reducing the risk of cerebrovascular accidents. Intravenous Labetalol, Nifedipine or hydralazine are the drugs most commonly used to manage preeclampsia but there is insignificant evidence to indicate which drug is preferable..

Magnesium sulfate is the treatment of choice for the prevention and treatment of eclamptic seizures Where immediate child-birth is not essential, a delay of 24 hours will allow steroids to be given to mature the baby's lungs, although a shorter duration may still be of benefit.

Preeclampsia is associated with short-term and long-term maternal and fetal complications. For the mother, it may lead to eclamptic seizures, stroke, intracranial bleed, uncontrolled hypertension, renal failure, and hemolysis. For the fetus, it may lead to intrauterine growth restriction, placental abruption, and the short-term and long-term complications of prematurity, as well as predisposition to adult cardiovascular and metabolic disorders. Currently, there is no effective therapy to preeclampsia, and delivery remains the only approach to preventing maternal morbidity and mortality. However, this is usually achieved at the expense of premature delivery and its associated morbidities. Moreover, following the delivery, preeclampsia resolved slowly within days, exposing the mother to late complications and increasing treatment cost significantly.

To date, the exact etiology of preeclampsia remains unknown. However, evidence obtained in recent years, supports the theory that angiogenic imbalance is the end common pathway that leads to clinical preeclampsia. During normal pregnancy, vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) promote pro-angiogenic state that regulates vascular tone and glomerular capillary health. In preeclampsia, these proteins are antagonized by excessive placental production of soluble fms-like tyrosine kinase-1 (sFlt-1), thereby creating angiogenic imbalance. After delivery, this imbalance resolves within hours to days correlating with the resolution of the disease. One of the observations that marked sFlt-1 as key player in the pathogenesis of preeclampsia was made in an animal model. It was demonstrated that preeclampsia can be induced in animal model by over expressing sFlt-1 alone. In their model hydrophilic statins treatment decreased sFlt-1 levels and up-regulated VEGF and PlGF levels. Most importantly, statins ameliorated preeclampsia symptoms by improving hypertension and proteinuria in the preeclamptic mice.

Statins are potent inhibitors of cholesterol biosynthesis and used successfully in the primary and secondary prevention of coronary heart disease. Additionally, statins are known to mediate pleiotropic effects via improving endothelial function and attenuating inflammatory responses. Rosuvastatin is a hydrophilic statin, characterized by low permeability through membranes, as the placenta and blood-brain-barrier. In addition, Short treatment (hours to days) with this type of statin improved the outcome of patients during acute myocardial infarction, sepsis, contrast-induced nephropathy, hepatic ischemia/reperfusion injury, emphasizing its preferential pleiotropic effects.

Currently, the food and drug administration classifies all statins as pregnancy category X and discourages their use during pregnancy due to higher abortion rate and teratogenicity that were observed in animals exposed to hydrophobic statins during pregnancy. Evidence for teratogenicity of the hydrophilic statins was never reported probably due to their limited permeability across membranes. Since the use of statins after delivery is allowed, the present study will aim to evaluate whether Rosuvastatin may accelerates preeclampsia resolution following delivery and potentially reduce postpartum preeclampsia complications.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Condition  ICMJE Severe Pre-eclampsia
Intervention  ICMJE
  • Drug: Rosuvastatin
    Rosuvastatin is a hydrophilic statin, short treatment (hours to days) with this type of statin improved the outcome of patients during acute myocardial infarction, sepsis, contrast-induced nephropathy, hepatic ischemia/reperfusion injury, emphasizing its preferential pleiotropic effects. Currently, the FDA classifies all statins as pregnancy category X and discourages their use during pregnancy due to higher abortion rate and teratogenicity that were observed in animals exposed to hydrophobic statins during pregnancy. Since the use of statins after delivery is allowed, the present study will aim to evaluate whether Rosuvastatin may accelerates preeclampsia resolution following delivery and potentially reduce postpartum preeclampsia complications.
    Other Name: Stator
  • Drug: Placebo
Study Arms  ICMJE
  • Placebo Comparator: control

    After signing an informed consent form and filling a demographic and medical questionnaire, a randomization 1:1 will be carried. 50 women will be in the control arm. the group will be treated according to ACOG guidelines (Appendix). After the delivery, a small placenta sample will be collected.

    Control group will be treated with placebo.

    Intervention: Drug: Placebo
  • Experimental: treatment
    50 women will be in the treatment arm. the group will be treated according to ACOG guidelines (Appendix). After the delivery, a small placenta sample will be collected. In addition, following randomization experimental group will be treated with Rosuvastatin 40mg that will be administrated orally with or without food. Treatment will be carried within the first hour following delivery. Another dose will be given 24 hours after first administration. Control group will be treated with placebo.
    Intervention: Drug: Rosuvastatin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: December 10, 2014)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2016
Estimated Primary Completion Date July 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Women who understand and sign the informed consent form.
  2. Women over the age of 18.
  3. Women between 24+0 weeks and 41+6 weeks gestation
  4. Women with singleton viable pregnancy.
  5. Have a diagnosis of severe pre-eclampsia

Exclusion Criteria:

  1. Eclampsia (convulsions)
  2. Current use of statins
  3. Women during active labor (5 cm and above)
  4. Contraindications to statin use (other than pregnancy) including:

    • Hypersensitivity to Rosuvastatin or any of its excipients
    • Active liver disease or elevation of serum Transaminases >3 ULN) believed to be unrelated to pre- eclampsia.
    • Pre-pregnant renal insufficiency (creatine clearance less than 30 ml/min)
    • Concomitant administration of medications known to interact with Rosuvastatin (e.g. Cimetidine)
  5. A known or suspected adverse reaction in former statin use.
  6. Transfer to a non-trial centre
  7. Women who would like to breastfeed 24-48 hours after delivery
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02314286
Other Study ID Numbers  ICMJE sor005514ctil
SCRC14001 ( Other Identifier: soroka )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ofer Beharier, Soroka University Medical Center
Study Sponsor  ICMJE Soroka University Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Soroka University Medical Center
Verification Date December 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP