<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01717586</url>
  </required_header>
  <id_info>
    <org_study_id>12-097 OPRU/OPRC Pravastatin</org_study_id>
    <secondary_id>U54HD047891</secondary_id>
    <nct_id>NCT01717586</nct_id>
  </id_info>
  <brief_title>Pravastatin for Prevention of Preeclampsia</brief_title>
  <acronym>Statin</acronym>
  <official_title>Pravastatin for the Prevention of Preeclampsia in High-Risk Women: A Phase I Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The University of Texas Medical Branch, Galveston</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Pittsburgh</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Northwestern University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>The University of Texas Medical Branch, Galveston</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary purpose of this pilot study is to determine the pharmacokinetic (PK) parameters&#xD;
      and collect preliminary safety data for pravastatin when used as a prophylactic daily&#xD;
      treatment in pregnant women at high risk of preeclampsia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Preeclampsia shares pathogenic similarities with adult cardiovascular diseases as well as&#xD;
      many risk factors. Endothelial dysfunction and inflammation are fundamental for the&#xD;
      initiation and progression of both. There is strong evidence that&#xD;
      3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are beneficial&#xD;
      in primary and secondary prevention of cardiovascular mortality and other cardiovascular&#xD;
      events. Biological plausibility as well as animal data supports a similar role for statins in&#xD;
      preeclampsia.&#xD;
&#xD;
      Currently, there are no clinically available agents to prevent preeclampsia. However because&#xD;
      of the below properties of statins, this class of medications could substantially contribute&#xD;
      to preeclampsia prevention.&#xD;
&#xD;
        1. Statins pleiotropic actions on various mechanisms: reversing the angiogenic imbalance by&#xD;
           upregulating vascular endothelial growth factor (VEGF) and placental growth factor&#xD;
           (PlGF), and reducing the antiangiogenic factors such as soluble fms-like tyrosine&#xD;
           kinase-1 (sFlt-1) and soluble endoglin (sEng).&#xD;
&#xD;
        2. Statins up regulation of endothelial nitric oxide synthase, leading to improved nitric&#xD;
           oxide production in the vasculature and to activate the heme oxygenase-1/carbon monoxide&#xD;
           (HO-1/CO) pathway, protecting the endothelium and reducing the inflammatory and&#xD;
           oxidative insults.&#xD;
&#xD;
      The purpose of this pilot study is to evaluate the maternal-fetal safety and pharmacokinetic&#xD;
      (PK) profiles of pravastatin when used in pregnant women at high-risk of developing&#xD;
      preeclampsia.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Anticipated">December 2025</completion_date>
  <primary_completion_date type="Anticipated">December 2025</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number and type of maternal adverse events</measure>
    <time_frame>From the date of randomization until the date of delivery, assessed up to 210 days</time_frame>
    <description>The presence of side effects and adverse events will be assessed at each study visit by:&#xD;
a symptoms checklist&#xD;
any other report of adverse events&#xD;
at select visits: laboratory testing for liver function test(LFT) and creatine kinase(CK)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number and type of fetal/neonatal adverse events</measure>
    <time_frame>From date of birth up to discharge or 120 days after birth.</time_frame>
    <description>The presence of adverse events will be assessed by evaluating&#xD;
Fetal and neonatal death&#xD;
Birthweight (including rate of small for gestational age)&#xD;
Apgar scores&#xD;
Congenital malformations&#xD;
Auditory brainstem response (ABR) evoked potential&#xD;
Cord blood lipid profile, AST/ALT, and CK levels</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic parameters of pravastatin sodium during pregnancy</measure>
    <time_frame>Between Pre-dose (0) and 24 hours post dose</time_frame>
    <description>Timed blood and urine collection performed once between 18 wks 0 days GA and 23 wks 6 days GA and once between 30 wks 0 days GA and 33 wks 6 days GA.&#xD;
Timed blood collection intervals: pre-dose(0)and 0.5hr, 1hr, 1.5hr, 2hr, 3hr, 4hr, 6hr, 8hr post dose.&#xD;
Time urine collection intervals: pre-dose (0) and 0-4hr, 4-8hr hr post dose.&#xD;
Evaluation parameters:Maximum observed plasma concentration (Cmax) and peak time (Tmax), Steady-state area under the plasma concentration-time curve during the 24-h dosing interval (AUC0-24h), Steady-state apparent oral clearance (CL/F), Elimination half-life (t½), Renal clearance of pravastatin</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">48</enrollment>
  <condition>Preeclampsia</condition>
  <arm_group>
    <arm_group_label>Pravastatin Group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Pregnant women at high-risk for preeclampsia who are taking pravastatin during their pregnancy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control Group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Pregnant women who are at high-risk for developing preeclampsia who are taking a placebo during their pregnancy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pravastatin</intervention_name>
    <description>Comparison of different drug dosages. Women will be instructed to take a pravastatin pill everyday starting the day of randomization and ending the day of delivery. The women will be divided into three cohorts. Each cohort will receive one of the following doses of pills: 10mg or 20mg or 40mg.</description>
    <arm_group_label>Pravastatin Group</arm_group_label>
    <other_name>pravastatin sodium</other_name>
    <other_name>Brand name: Pravachol®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Women will be instructed to take a placebo pill daily beginning the day of randomization and ending the day of delivery.</description>
    <arm_group_label>Control Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Documented history (review of chart or delivery note) of prior severe early onset PE in a&#xD;
        prior pregnancy and requiring delivery ≤340/7 weeks' gestation. If in the index pregnancy,&#xD;
        the woman was induced at the upper limit of 34 0/7 weeks of pregnancy and delivered within&#xD;
        48 hours in the same hospitalization, that woman could be enrolled. Women with severe PE in&#xD;
        a pregnancy remote (greater than 2 pregnancies removed) from the current pregnancy do not&#xD;
        qualify.&#xD;
&#xD;
          -  18 years or older with the ability to give informed consent&#xD;
&#xD;
          -  Singleton pregnancy&#xD;
&#xD;
          -  Normal serum transaminase (ALT and AST) concentrations in the last 6-months&#xD;
&#xD;
          -  Gestational age (GA) between 12 weeks 0 days to 16 weeks 6 days based on clinical&#xD;
             information and confirmed by an ultrasound per study procedures.&#xD;
&#xD;
          -  Willingness to participate in planned PK study visits&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Known chromosomal, genetic, or major fetal malformations, fetal demise, or planned&#xD;
        termination&#xD;
&#xD;
          -  Patients with contraindications for statin therapy:&#xD;
&#xD;
          -  Hypersensitivity to pravastatin or any component of the product&#xD;
&#xD;
          -  Active liver disease (acute hepatitis, chronic active hepatitis, persistently abnormal&#xD;
             liver enzymes (2 x normal of serum transaminases)&#xD;
&#xD;
          -  History of myopathy or rhabdomyolysis&#xD;
&#xD;
          -  Patients with any of the following conditions:&#xD;
&#xD;
          -  HIV positive&#xD;
&#xD;
          -  Status post solid organ transplant&#xD;
&#xD;
          -  Chronic renal disease/insufficiency with baseline serum creatinine ≥1.5 mg/dL&#xD;
&#xD;
          -  Uterine malformations (didelphus, bicornuate, unicornate)&#xD;
&#xD;
          -  Cancer&#xD;
&#xD;
          -  Statin use in current pregnancy&#xD;
&#xD;
          -  Current use of medications with potential drug interactions with statins, such as&#xD;
             cyclosporine, fibrates, gemfibrozil, niacin, erythromycin, fluconazole, itraconazole,&#xD;
             cholestyramine, digoxin, rifampin (patients will not be excluded if the drug has been&#xD;
             discontinued, or is prescribed for a short duration of time)&#xD;
&#xD;
          -  Participating in another intervention study that influences the outcomes of this study&#xD;
&#xD;
          -  Plans to deliver in a non-network site&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Maged Costantine, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UTexasGalveston; Ohio State</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Northwestern University</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas Medical Branch</name>
      <address>
        <city>Galveston</city>
        <state>Texas</state>
        <zip>77555</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Costantine MM, Cleary K, Hebert MF, Ahmed MS, Brown LM, Ren Z, Easterling TR, Haas DM, Haneline LS, Caritis SN, Venkataramanan R, West H, D'Alton M, Hankins G; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Units Network. Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am J Obstet Gynecol. 2016 Jun;214(6):720.e1-720.e17. doi: 10.1016/j.ajog.2015.12.038. Epub 2015 Dec 23.</citation>
    <PMID>26723196</PMID>
  </reference>
  <reference>
    <citation>Costantine MM, West H, Wisner KL, Caritis S, Clark S, Venkataramanan R, Stika CS, Rytting E, Wang X, Ahmed MS; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Centers (OPRC) Network, Bethesda, MD. A randomized pilot clinical trial of pravastatin versus placebo in pregnant patients at high risk of preeclampsia. Am J Obstet Gynecol. 2021 Dec;225(6):666.e1-666.e15. doi: 10.1016/j.ajog.2021.05.018. Epub 2021 May 24.</citation>
    <PMID>34033812</PMID>
  </reference>
  <reference>
    <citation>Costantine MM, Cleary K; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units Network*. Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obstet Gynecol. 2013 Feb;121(2 Pt 1):349-353. doi: 10.1097/AOG.0b013e31827d8ad5.</citation>
    <PMID>23344286</PMID>
  </reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>January 3, 2012</study_first_submitted>
  <study_first_submitted_qc>October 26, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 30, 2012</study_first_posted>
  <last_update_submitted>March 20, 2023</last_update_submitted>
  <last_update_submitted_qc>March 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>preeclampsia</keyword>
  <keyword>pravastatin</keyword>
  <keyword>Pravachol®</keyword>
  <keyword>statin</keyword>
  <keyword>high-risk pregnancy</keyword>
  <keyword>safety</keyword>
  <keyword>fetal morbidity and mortality</keyword>
  <keyword>maternal morbidity and mortality</keyword>
  <keyword>neonatal mortality</keyword>
  <keyword>premature delivery</keyword>
  <keyword>preemie</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pre-Eclampsia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pravastatin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>per NICHD guidelines</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01717586
org study id: 12-097 OPRU/OPRC Pravastatin
secondary id: U54HD047891
nct id: NCT01717586
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
The primary purpose of this pilot study is to determine the pharmacokinetic (PK) parameters
      and collect preliminary safety data for pravastatin when used as a prophylactic daily
      treatment in pregnant women at high risk of preeclampsia.
Preeclampsia shares pathogenic similarities with adult cardiovascular diseases as well as
      many risk factors. Endothelial dysfunction and inflammation are fundamental for the
      initiation and progression of both. There is strong evidence that
      3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are beneficial
      in primary and secondary prevention of cardiovascular mortality and other cardiovascular
      events. Biological plausibility as well as animal data supports a similar role for statins in
      preeclampsia.

      Currently, there are no clinically available agents to prevent preeclampsia. However because
      of the below properties of statins, this class of medications could substantially contribute
      to preeclampsia prevention.

        1. Statins pleiotropic actions on various mechanisms: reversing the angiogenic imbalance by
           upregulating vascular endothelial growth factor (VEGF) and placental growth factor
           (PlGF), and reducing the antiangiogenic factors such as soluble fms-like tyrosine
           kinase-1 (sFlt-1) and soluble endoglin (sEng).

        2. Statins up regulation of endothelial nitric oxide synthase, leading to improved nitric
           oxide production in the vasculature and to activate the heme oxygenase-1/carbon monoxide
           (HO-1/CO) pathway, protecting the endothelium and reducing the inflammatory and
           oxidative insults.

      The purpose of this pilot study is to evaluate the maternal-fetal safety and pharmacokinetic
      (PK) profiles of pravastatin when used in pregnant women at high-risk of developing
      preeclampsia.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Number and type of maternal adverse events
time frame: From the date of randomization until the date of delivery, assessed up to 210 days
description: The presence of side effects and adverse events will be assessed at each study visit by:
a symptoms checklist
any other report of adverse events
at select visits: laboratory testing for liver function test(LFT) and creatine kinase(CK)
measure: Number and type of fetal/neonatal adverse events
time frame: From date of birth up to discharge or 120 days after birth.
description: The presence of adverse events will be assessed by evaluating
Fetal and neonatal death
Birthweight (including rate of small for gestational age)
Apgar scores
Congenital malformations
Auditory brainstem response (ABR) evoked potential
Cord blood lipid profile, AST/ALT, and CK levels
measure: Pharmacokinetic parameters of pravastatin sodium during pregnancy
time frame: Between Pre-dose (0) and 24 hours post dose
description: Timed blood and urine collection performed once between 18 wks 0 days GA and 23 wks 6 days GA and once between 30 wks 0 days GA and 33 wks 6 days GA.
Timed blood collection intervals: pre-dose(0)and 0.5hr, 1hr, 1.5hr, 2hr, 3hr, 4hr, 6hr, 8hr post dose.
Time urine collection intervals: pre-dose (0) and 0-4hr, 4-8hr hr post dose.
Evaluation parameters:Maximum observed plasma concentration (Cmax) and peak time (Tmax), Steady-state area under the plasma concentration-time curve during the 24-h dosing interval (AUC0-24h), Steady-state apparent oral clearance (CL/F), Elimination half-life (t½), Renal clearance of pravastatin
arm group label: Pravastatin Group
arm group type: Active Comparator
description: Pregnant women at high-risk for preeclampsia who are taking pravastatin during their pregnancy.
arm group label: Control Group
arm group type: Placebo Comparator
description: Pregnant women who are at high-risk for developing preeclampsia who are taking a placebo during their pregnancy.
intervention type: Drug
intervention name: Pravastatin
description: Comparison of different drug dosages. Women will be instructed to take a pravastatin pill everyday starting the day of randomization and ending the day of delivery. The women will be divided into three cohorts. Each cohort will receive one of the following doses of pills: 10mg or 20mg or 40mg.
arm group label: Pravastatin Group
other name: pravastatin sodium
other name: Brand name: Pravachol®
intervention type: Drug
intervention name: Placebo
description: Women will be instructed to take a placebo pill daily beginning the day of randomization and ending the day of delivery.
arm group label: Control Group
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Maged Costantine, MD
role: Principal Investigator
affiliation: UTexasGalveston; Ohio State
facility: 
facility: 
facility: 
country: United States
citation: Costantine MM, Cleary K, Hebert MF, Ahmed MS, Brown LM, Ren Z, Easterling TR, Haas DM, Haneline LS, Caritis SN, Venkataramanan R, West H, D'Alton M, Hankins G; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Units Network. Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am J Obstet Gynecol. 2016 Jun;214(6):720.e1-720.e17. doi: 10.1016/j.ajog.2015.12.038. Epub 2015 Dec 23.
PMID: 26723196
citation: Costantine MM, West H, Wisner KL, Caritis S, Clark S, Venkataramanan R, Stika CS, Rytting E, Wang X, Ahmed MS; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Centers (OPRC) Network, Bethesda, MD. A randomized pilot clinical trial of pravastatin versus placebo in pregnant patients at high risk of preeclampsia. Am J Obstet Gynecol. 2021 Dec;225(6):666.e1-666.e15. doi: 10.1016/j.ajog.2021.05.018. Epub 2021 May 24.
PMID: 34033812
citation: Costantine MM, Cleary K; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units Network*. Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obstet Gynecol. 2013 Feb;121(2 Pt 1):349-353. doi: 10.1097/AOG.0b013e31827d8ad5.
PMID: 23344286
responsible party type: Sponsor
mesh term: Pre-Eclampsia
mesh term: Pravastatin
sharing ipd: No
ipd description: per NICHD guidelines