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Second-Line Uterotonics in Postpartum Hemorrhage: A Randomized Clinical Trial

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ClinicalTrials.gov Identifier: NCT03584854
Recruitment Status : Recruiting
First Posted : July 12, 2018
Last Update Posted : June 27, 2019
Sponsor:
Information provided by (Responsible Party):
Naida Margaret Cole, Brigham and Women's Hospital

Brief Summary:
The aim of this study is to evaluate in a randomized fashion the comparative efficacy of two second-line medications, methylergonovine and carboprost for treating atonic postpartum hemorrhage (PPH). The investigators hypothesize that administration of methylergonovine will produce superior uterine tone to carboprost in atonic PPH.

Condition or disease Intervention/treatment Phase
Postpartum Hemorrhage Uterine Atony Drug: 15-methyl prostaglandin F2α Drug: Methylergonovine Maleate Phase 4

Detailed Description:

Primary postpartum hemorrhage (PPH) is defined by the American College of Obstetricians and Gynecologists as a cumulative blood loss of >1000 mL within 24 hours of the birth process. PPH remains a leading source of maternal morbidity and mortality worldwide with uterine atony identified as the underlying cause in up to 80% of cases. Between 1994 and 2006, the rate of PPH increased by 26% in the United States, raising further concern for this problem.

Treatment of PPH typically begins with administration of exogenous oxytocin, a hormone responsible for uterine contraction. When postpartum bleeding persists despite oxytocin administration, a multidisciplinary approach combining mechanical, pharmacologic, and surgical measures is indicated. Approximately 3-25% of PPH cases require a second-line uterotonic agent in addition to oxytocin, with the two most commonly administered second-line agents in the U.S.A. being methylergonovine maleate (methylergonovine) and 15-methyl prostaglandin F2α (carboprost). The comparative efficacy of these two drugs is unknown and the most recent American College of Obstetricians and Gynecologists Practice Bulletin makes no recommendation on which second-line uterotonic agents to administer preferentially in the absence of contraindications.

This study will evaluate in a randomized fashion the comparative efficacy of methylergonovine and carboprost for treating atonic PPH. Patients undergoing non-emergent cesarean section (C/S) with uterine atony and no contraindications to either drug will be randomized to receive one of the two equivalent agents in a blinded fashion after oxytocin. After ten minutes, their uterine tone will be assessed by the obstetrician and reported on a 0-10 point scale.

A power calculation was performed to detect a mean difference in uterine tone between groups of 1 point on a 0-10 point scale with 80% power and significance level of 0.05. The investigators estimate 37 patients will be required in each arm. Allowing for a 20% rate of withdrawals or missing information, a total of 100 patients will be enrolled in this study.

Investigators will adhere to the FDA Expedited Safety Requirements in reporting any adverse event that is serious, unexpected, and associated with the use of the study drugs. Any such adverse event will be reported to the study site Institutional Review Board (IRB) and serious events will prompt the study to be halted until further discussion with the IRB.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Second-Line Uterotonics in Postpartum Hemorrhage: A Randomized Clinical Trial
Actual Study Start Date : March 1, 2019
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : March 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 15-methyl prostaglandin F2α
IM Carboprost followed by Methylergonovine if needed.
Drug: 15-methyl prostaglandin F2α
Participants will receive standard intraoperative care including an infusion of oxytocin immediately postpartum. If a second-line uterotonic is requested, patients randomized to the "carboprost" study group will receive an intramuscular dose of 0.25mg (1mL) carboprost. If another second-line uterotonic is requested, the patients will receive 0.2mg (1mL) intramuscular methylergonovine.
Other Name: Carboprost

Drug: Methylergonovine Maleate
Participants will receive standard intraoperative care including an infusion of oxytocin immediately postpartum. If a second-line uterotonic is requested, patients randomized to the "methergine" study group will receive an intramuscular dose of 0.2mg (1mL) methylergonovine. If another second-line uterotonic is requested, the patients will receive 0.25mg (1mL) intramuscular carboprost.
Other Name: Methylergonovine

Active Comparator: Methylergonovine Maleate
IM Methylergonovine followed by Carboprost if needed.
Drug: 15-methyl prostaglandin F2α
Participants will receive standard intraoperative care including an infusion of oxytocin immediately postpartum. If a second-line uterotonic is requested, patients randomized to the "carboprost" study group will receive an intramuscular dose of 0.25mg (1mL) carboprost. If another second-line uterotonic is requested, the patients will receive 0.2mg (1mL) intramuscular methylergonovine.
Other Name: Carboprost

Drug: Methylergonovine Maleate
Participants will receive standard intraoperative care including an infusion of oxytocin immediately postpartum. If a second-line uterotonic is requested, patients randomized to the "methergine" study group will receive an intramuscular dose of 0.2mg (1mL) methylergonovine. If another second-line uterotonic is requested, the patients will receive 0.25mg (1mL) intramuscular carboprost.
Other Name: Methylergonovine




Primary Outcome Measures :
  1. Uterine Tone [ Time Frame: at 10 minutes following administration of the first study drug ]
    Uterine contractile tone will be measured on a 0-10 score as assessed by the obstetrician; 0 is 'no tone', 10 is 'perfect tone' or 'excellent tone'


Secondary Outcome Measures :
  1. Uterine Tone [ Time Frame: at 5 minutes following administration of the first study drug ]
    Uterine contractile tone will be measured on a 0-10 score as assessed by the obstetrician; 0 is 'no tone', 10 is 'perfect tone' or 'excellent tone'

  2. Additional Uterotonic [ Time Frame: from time of delivery until surgery completion ]
    An additional second-line uterotonic which is given in the operating room after administration of the first study drug

  3. Transfusion [ Time Frame: within the first 24 hours after delivery of the fetus ]
    The number of blood products transfused for anemia due to postpartum blood loss

  4. Additional Intervention [ Time Frame: within the first 24 hours after delivery of the fetus ]
    The need for an additional surgical or radiologic intervention to control postpartum hemorrhage

  5. Quantitative Blood Loss (QBL) [ Time Frame: within the first 24 hours after delivery of the fetus ]
    The total volume of blood loss measured by a QBL scale weighing surgical drapes, towels, sponges and suction fluid

  6. Hematocrit Drop [ Time Frame: from time of preoperative hematocrit value closest to delivery until time of first postoperative hematocrit ]
    Comparison of the preoperative and first postoperative hematocrit values

  7. Length of Hospital Stay [ Time Frame: from day of surgery to day of hospital discharge ]
    Total duration of hospital stay (in days) after cesarean delivery

  8. Maternal Morbidity [ Time Frame: from time of delivery until time of hospital discharge ]
    Any unplanned adverse reaction or event with clinical consequences e.g. cardiovascular event, intubation, ICU admission, hypovolemic shock or adverse study drug reaction



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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   pregnant women
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • pregnant with a fetus >/=24 weeks gestational age
  • non-emergent cesarean delivery
  • postpartum hemorrhage deemed the result of uterine atony

Exclusion Criteria:

  • non-English speaking patients requiring an interpreter
  • any hypertensive disorder
  • cardiovascular disease
  • asthma
  • refusal of transfused blood products
  • coagulopathy or abnormal coagulation lab values
  • hypersensitivity to methylergonovine maleate or 15-methyl prostaglandin

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03584854


Contacts
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Contact: Naida M Cole, MD 617-732-8210 nmcole@bwh.harvard.edu
Contact: Brian T Bateman, MD, MSc 617-732-8210 bbateman@bwh.harvard.edu

Locations
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United States, Massachusetts
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Naida M Cole, MD       nmcole@partners.org   
Sponsors and Collaborators
Brigham and Women's Hospital
Investigators
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Principal Investigator: Naida M Cole, MD Brigham and Women's Hospital, 75 Francis Street, Boston MA 02115

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Responsible Party: Naida Margaret Cole, Principal Investigator, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT03584854     History of Changes
Other Study ID Numbers: 2018P000776
First Posted: July 12, 2018    Key Record Dates
Last Update Posted: June 27, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data from this study will be de-identified and prepared in an anonymous data pack to minimize the possibility of re-identification. In the interests of the public good, ethical transparency, and economic and scientific support of future research, the data pack will be available to all appropriate requestors. The data will be shared in a secure fashion to protect the privacy of participants.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: The data will be available upon publication of the study and for 10 years thereafter.
Access Criteria: Data requestors will be required to provide a detailed IRB-approved study protocol, data collection tools to be used and planned statistical analysis to the data generator. Citation of the data generator will be required if the data is used in a peer-reviewed publication.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
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Postpartum Hemorrhage
Uterine Inertia
Hemorrhage
Pathologic Processes
Obstetric Labor Complications
Pregnancy Complications
Puerperal Disorders
Uterine Hemorrhage
Dystocia
Methylergonovine
Dinoprost
Dinoprost tromethamine
Carboprost
Carboprost tromethamine
Maleic acid
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Oxytocics
Reproductive Control Agents
Physiological Effects of Drugs
Abortifacient Agents, Nonsteroidal
Abortifacient Agents