<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/NCT03303235</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00120873</org_study_id>
    <nct_id>NCT03303235</nct_id>
  </id_info>
  <brief_title>Intravenous Versus Intramuscular Administration of Methylergonovine for Uterine Contraction in Cesarean Sections</brief_title>
  <official_title>How's the Tone? Intravenous Versus Intramuscular Administration of Methylergonovine for Uterine Contraction in Cesarean Sections</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Johns Hopkins University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Johns Hopkins University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Insufficient uterine tone resulting in atony can potentiate hemorrhage and adverse outcomes&#xD;
      for the parturient. Oxytocin is the first pharmacologic agent used, followed by&#xD;
      methylergonovine, carboprost, and misoprostol. The American Congress of Obstetricians and&#xD;
      Gynecologists (ACOG) recommends the sequential use of oxytocin, followed by methylergonovine,&#xD;
      carboprost, misoprostol, then surgical intervention for cases of refractory uterine atony.&#xD;
      Many studies have examined the effect and dosage of intravenous uterotonics, including&#xD;
      oxytocin.&#xD;
&#xD;
      Although there are anecdotal reports of using intravenous bolus or rapid infusion of&#xD;
      methylergonovine, no randomized trial has compared efficacy and side effects of these two&#xD;
      routes of administration. Investigators hypothesize that intravenous methylergonovine reduces&#xD;
      the time to adequate uterine tone (the tone at which the uterus is adequately contracted to&#xD;
      prevent atony after delivery of neonate), decreases the total dose of methylergonovine to&#xD;
      contract the uterus, and therefore produces fewer side effects of hypertension, nausea, and&#xD;
      vomiting. Reducing the time to achieve adequate uterine tone is likely to decrease postpartum&#xD;
      hemorrhage.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The United States is one of the few modern countries in which maternal peripartum mortality&#xD;
      continues to rise. One of the three most important causes of maternal mortality is severe&#xD;
      hemorrhage. Controlling postpartum uterine tone remains an important role for the obstetric&#xD;
      anesthesiologist. Insufficient uterine tone resulting in atony can potentiate hemorrhage and&#xD;
      adverse outcomes for the parturient. Oxytocin is the first pharmacologic agent used, followed&#xD;
      by methylergonovine, carboprost, and misoprostol. The American Congress of Obstetricians and&#xD;
      Gynecologists (ACOG) recommends the sequential use of oxytocin, followed by methylergonovine,&#xD;
      carboprost, misoprostol, then surgical intervention for cases of refractory uterine atony.&#xD;
      Many studies have examined the effect and dosage of intravenous uterotonics, including&#xD;
      oxytocin.&#xD;
&#xD;
      Methylergonovine maleate is a semi-synthetic ergot alkaloid. Methylergonovine(200 mcg) is&#xD;
      administered intramuscularly when oxytocin has been administered but has not contracted the&#xD;
      uterus sufficiently. It is not without side effects, however. Due to its vasoconstrictive&#xD;
      properties, methylergonovine has been shown to elevate blood pressures and is avoided in&#xD;
      preeclamptic patients who may not tolerate abrupt increases in blood pressures. Although&#xD;
      there are anecdotal reports of using intravenous bolus or rapid infusion of methylergonovine,&#xD;
      no randomized trial has compared efficacy and side effects of these two routes of&#xD;
      administration. Investigators hypothesize that intravenous methylergonovine reduces the time&#xD;
      to adequate uterine tone (the tone at which the uterus is adequately contracted to prevent&#xD;
      atony after delivery of neonate), decreases the total dose of methylergonovine to contract&#xD;
      the uterus, and therefore produces fewer side effects of hypertension, nausea, and vomiting.&#xD;
      Reducing the time to achieve adequate uterine tone is likely to decrease postpartum&#xD;
      hemorrhage.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Collaborators left the institution.&#xD;
  </why_stopped>
  <start_date type="Anticipated">July 2020</start_date>
  <completion_date type="Anticipated">December 2020</completion_date>
  <primary_completion_date type="Anticipated">October 2020</primary_completion_date>
  <phase>Early 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>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Outcomes Assessor)</masking>
    <masking_description>The patient and obstetrician will all be blinded to group assignments. The anesthesiologist will make and administer the medication, as it is important for timely administration of the methylergonovine when it is asked to be used. The anesthesiologist directly taking care of the patient will not be blinded.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Time to achieve &quot;adequate&quot; uterine tone</measure>
    <time_frame>10 minutes</time_frame>
    <description>Our primary objective is to determine the time to achieve &quot;adequate&quot; uterine tone with either intramuscular (IM) dose versus intravenous (IV) dose methylergonovine, when oxytocin has failed to do so in cesarean sections.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Dose that achieves &quot;adequate&quot; uterine tone</measure>
    <time_frame>3 minutes</time_frame>
    <description>Determining dose that achieves &quot;adequate&quot; uterine tone as defined by obstetricians on a qualitative numerical scale defined prior to the study (0 to 10 with 0 being inability of uterus to contract (i.e. uterine atony) to 10 being fully contracting uterus; &quot;adequate&quot; would be &gt;5 on the scale)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need for additional uterotonic agents</measure>
    <time_frame>3 minutes</time_frame>
    <description>Quantifying need for additional uterotonic agents as outlined by the postpartum hemorrhage guidelines set forth by ACOG</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of side effects of methylergonovine</measure>
    <time_frame>30 minutes</time_frame>
    <description>Determining frequency of side effects of methylergonovine, including blood pressure changes, especially if elevated &gt;20% preoperative level), headache, nausea, and vomiting</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need for vasopressors</measure>
    <time_frame>3 minutes</time_frame>
    <description>To determine if the patient requires a vasopressor (including phenylephrine, ephedrine, epinephrine, norepinephrine or vasopressin)?</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Estimated blood loss</measure>
    <time_frame>2 hours</time_frame>
    <description>Utilizing estimated blood loss by suction canister + estimated weight of blood on surgical lap</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Computed blood loss</measure>
    <time_frame>2 hours</time_frame>
    <description>Calculating changes in hematocrit (Hct preop - Hct postop)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Uterine Atony</condition>
  <condition>Uterine Tone Disorders</condition>
  <condition>Postpartum Hemorrhage</condition>
  <arm_group>
    <arm_group_label>IV Methergine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>IV methylergonovine group&#xD;
-IM 0.9% NaCl (1 ml)) + IV methylergonovine (2 mcg/ml) infusion (100 ml)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Conventional</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>IM methylergonovine group&#xD;
-200 mcg IM methylergonovine (1 ml) + IV 0.9% NaCl infusion (100 ml)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methylergonovine</intervention_name>
    <description>IV vs IM</description>
    <arm_group_label>Conventional</arm_group_label>
    <arm_group_label>IV Methergine</arm_group_label>
    <other_name>methergine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All patients admitted for elective cesarean section&#xD;
&#xD;
          -  All laboring patients for planned vaginal delivery as these women may have an&#xD;
             unplanned cesarean delivery for maternal or for fetal indications&#xD;
&#xD;
          -  Patients not in labor but admitted for non-elective cesarean section&#xD;
&#xD;
          -  Administration of oxytocin prior to administration of methylergonovine, in accordance&#xD;
             to the ACOG guideline for postpartum hemorrhage&#xD;
&#xD;
          -  Obstetrician's request for methylergonovine intraoperatively to the anesthesiologist&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Fetus not considered to be of viable gestational age by obstetrical team&#xD;
&#xD;
          -  Patients with hypertension (either chronic or pregnancy-induced, including&#xD;
             preeclampsia)&#xD;
&#xD;
          -  Patients with coronary artery disease, established and diagnosed by medical internist&#xD;
             or cardiologist&#xD;
&#xD;
          -  Patients taking CYP3A4 inhibitors&#xD;
&#xD;
          -  Patients taking beta blockers.&#xD;
&#xD;
          -  Patients with contraindications to any of the uterotonic agents for whatever medical&#xD;
             reason (allergies, for example)&#xD;
&#xD;
          -  Surgeon request for administration of methylergonovine earlier than per protocol due&#xD;
             to clinical situation as abovementioned&#xD;
&#xD;
          -  Maternal or obstetrician refusal&#xD;
&#xD;
          -  Patients who require obstetrical intervention before 30 minutes has elapsed&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Female parturients eligible to undergo a cesarean section</gender_description>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Karen Lindeman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Johns Hopkins Hospital</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>September 26, 2017</study_first_submitted>
  <study_first_submitted_qc>October 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 5, 2017</study_first_posted>
  <last_update_submitted>July 30, 2020</last_update_submitted>
  <last_update_submitted_qc>July 30, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 3, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>methylergonovine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Postpartum Hemorrhage</mesh_term>
    <mesh_term>Uterine Inertia</mesh_term>
    <mesh_term>Hemorrhage</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methylergonovine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </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/NCT03303235
org study id: IRB00120873
nct id: NCT03303235
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Insufficient uterine tone resulting in atony can potentiate hemorrhage and adverse outcomes
      for the parturient. Oxytocin is the first pharmacologic agent used, followed by
      methylergonovine, carboprost, and misoprostol. The American Congress of Obstetricians and
      Gynecologists (ACOG) recommends the sequential use of oxytocin, followed by methylergonovine,
      carboprost, misoprostol, then surgical intervention for cases of refractory uterine atony.
      Many studies have examined the effect and dosage of intravenous uterotonics, including
      oxytocin.

      Although there are anecdotal reports of using intravenous bolus or rapid infusion of
      methylergonovine, no randomized trial has compared efficacy and side effects of these two
      routes of administration. Investigators hypothesize that intravenous methylergonovine reduces
      the time to adequate uterine tone (the tone at which the uterus is adequately contracted to
      prevent atony after delivery of neonate), decreases the total dose of methylergonovine to
      contract the uterus, and therefore produces fewer side effects of hypertension, nausea, and
      vomiting. Reducing the time to achieve adequate uterine tone is likely to decrease postpartum
      hemorrhage.
The United States is one of the few modern countries in which maternal peripartum mortality
      continues to rise. One of the three most important causes of maternal mortality is severe
      hemorrhage. Controlling postpartum uterine tone remains an important role for the obstetric
      anesthesiologist. Insufficient uterine tone resulting in atony can potentiate hemorrhage and
      adverse outcomes for the parturient. Oxytocin is the first pharmacologic agent used, followed
      by methylergonovine, carboprost, and misoprostol. The American Congress of Obstetricians and
      Gynecologists (ACOG) recommends the sequential use of oxytocin, followed by methylergonovine,
      carboprost, misoprostol, then surgical intervention for cases of refractory uterine atony.
      Many studies have examined the effect and dosage of intravenous uterotonics, including
      oxytocin.

      Methylergonovine maleate is a semi-synthetic ergot alkaloid. Methylergonovine(200 mcg) is
      administered intramuscularly when oxytocin has been administered but has not contracted the
      uterus sufficiently. It is not without side effects, however. Due to its vasoconstrictive
      properties, methylergonovine has been shown to elevate blood pressures and is avoided in
      preeclamptic patients who may not tolerate abrupt increases in blood pressures. Although
      there are anecdotal reports of using intravenous bolus or rapid infusion of methylergonovine,
      no randomized trial has compared efficacy and side effects of these two routes of
      administration. Investigators hypothesize that intravenous methylergonovine reduces the time
      to adequate uterine tone (the tone at which the uterus is adequately contracted to prevent
      atony after delivery of neonate), decreases the total dose of methylergonovine to contract
      the uterus, and therefore produces fewer side effects of hypertension, nausea, and vomiting.
      Reducing the time to achieve adequate uterine tone is likely to decrease postpartum
      hemorrhage.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Outcomes Assessor)
masking description: The patient and obstetrician will all be blinded to group assignments. The anesthesiologist will make and administer the medication, as it is important for timely administration of the methylergonovine when it is asked to be used. The anesthesiologist directly taking care of the patient will not be blinded.
measure: Time to achieve "adequate" uterine tone
time frame: 10 minutes
description: Our primary objective is to determine the time to achieve "adequate" uterine tone with either intramuscular (IM) dose versus intravenous (IV) dose methylergonovine, when oxytocin has failed to do so in cesarean sections.
measure: Dose that achieves "adequate" uterine tone
time frame: 3 minutes
description: Determining dose that achieves "adequate" uterine tone as defined by obstetricians on a qualitative numerical scale defined prior to the study (0 to 10 with 0 being inability of uterus to contract (i.e. uterine atony) to 10 being fully contracting uterus; "adequate" would be >5 on the scale)
measure: Need for additional uterotonic agents
time frame: 3 minutes
description: Quantifying need for additional uterotonic agents as outlined by the postpartum hemorrhage guidelines set forth by ACOG
measure: Frequency of side effects of methylergonovine
time frame: 30 minutes
description: Determining frequency of side effects of methylergonovine, including blood pressure changes, especially if elevated >20% preoperative level), headache, nausea, and vomiting
measure: Need for vasopressors
time frame: 3 minutes
description: To determine if the patient requires a vasopressor (including phenylephrine, ephedrine, epinephrine, norepinephrine or vasopressin)?
measure: Estimated blood loss
time frame: 2 hours
description: Utilizing estimated blood loss by suction canister + estimated weight of blood on surgical lap
measure: Computed blood loss
time frame: 2 hours
description: Calculating changes in hematocrit (Hct preop - Hct postop)
arm group label: IV Methergine
arm group type: Experimental
description: IV methylergonovine group
-IM 0.9% NaCl (1 ml)) + IV methylergonovine (2 mcg/ml) infusion (100 ml)
arm group label: Conventional
arm group type: Active Comparator
description: IM methylergonovine group
-200 mcg IM methylergonovine (1 ml) + IV 0.9% NaCl infusion (100 ml)
intervention type: Drug
intervention name: Methylergonovine
description: IV vs IM
arm group label: Conventional
arm group label: IV Methergine
other name: methergine
criteria: 
gender: Female
gender based: Yes
gender description: Female parturients eligible to undergo a cesarean section
minimum age: N/A
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Karen Lindeman, MD
role: Principal Investigator
affiliation: Johns Hopkins University
facility: 
country: United States
responsible party type: Sponsor
mesh term: Postpartum Hemorrhage
mesh term: Uterine Inertia
mesh term: Hemorrhage
mesh term: Methylergonovine
sharing ipd: Undecided