Second-Line Uterotonics in Postpartum Hemorrhage: A Randomized Clinical Trial
Phase: PHASE4
Conditions: Postpartum Hemorrhage, Uterine Atony
Sponsor: Brigham and Women's Hospital

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Title: Second-line Uterotonics in Postpartum Hemorrhage: A Randomized Clinical Trial  
Sponsor Name: None  
PI Name: Kim, Jimin  
Protocol #: 2018P000775 
Type: Current View  
Date Received: April 04, 2018  
 
Study Staff 
 
Name 
Role 
Degree 
Organization 
Citi Certified  
Abel, Samantha 
Co-Investigator 
 
Mass General Brigham 
04/27/21 
Carusi, Daniela 
Co-Investigator 
MD, MSC 
BWH > Obstetrics/Gynecology 
01/25/22 
Chyan, Arthur 
Co-Investigator 
 
Mass General Brigham 
07/27/20 
Combs, David 
Co-Investigator 
 
MGH > Anesthesia 
04/10/20 
Corey, Sarah 
Research 
Assistant 
Ph.D 
BWH > Anesthesia 
11/21/19 
Farber, Michaela 
Co-Investigator 
MD, MS 
BWH > Anesthesia 
06/30/21 
Fields, Kara 
Statistician 
 
Mass General Brigham 
09/08/21 
Gran, Monica 
Co-Investigator 
 
Mass General Brigham 
08/24/21 
Hale, John 
Co-Investigator 
 
Mass General Brigham 
08/06/21 
Justice, Samuel 
Statistician 
 
Mass General Brigham 
09/03/21 
Kim, Jimin 
Principal 
Investigator 
 
BWH > Anesthesia 
08/13/19 
Lumbreras-
Marquez, Mario 
Co-Investigator 
 
BWH > Obstetrics/Gynecology > 
Other 
09/22/20 
Maeda, Ayumi 
Co-Investigator 
 
MGH > Anesthesia 
07/18/20 
Mendez-Pino, 
Laura 
Research 
Assistant 
MD 
Mass General Brigham 
04/19/22 
Mohammadi, 
Somayeh 
Co-Investigator 
 
Mass General Brigham 
06/17/21 
Murthy, Anarghya Research 
Assistant 
 
Mass General Brigham 
09/14/21 
Seifert, Sara 
Co-Investigator 
MD 
BWH > Anesthesia 
05/26/20 
Tsen, Lawrence 
Co-Investigator 
MD 
BWH > Anesthesia 
02/05/22 
Villela Franyutti, 
Diego 
Co-Investigator 
 
Mass General Brigham 
08/18/21 
Yanik, Michelle 
Co-Investigator 
 
Mass General Brigham 
08/24/21 
Zhou, Jie 
Co-Investigator 
MD, MS 
BWH > Anesthesia 
08/23/19 
 
Funding source 
 
Record # 
Fund 
Project 
Period 
PI Name 
Sponsor 
Record 
Type 
Process Link 
Date 
Link 
Status 
2019A009692 121504 
07/01/19-
06/30/21 
Cole, Naida 
M 
Brigham and 
Women's 
Hospital - 
Internal 
Funds 
RM – 
Funded 
Agreemen
t 
AME22 
12/26/19 Approved 
 
Other Agreements 
 
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Record # 
Fund 
Project 
Period 
PI Name 
Sponsor 
Record 
Type 
Process Link 
Date 
Link 
Status 
2022A006303  
 
Kim, Jimin 
Northwestern 
University 
RM – 
DUA In 
IR 
04/27/22 Approved 
Signatures 
PI Name: Bateman, Brian T, MD 
Authenticated: April 04, 2018 
 
Department Chair: Body, Simon C, MD, MPH 
Authenticated: April 04, 2018 
 
PI Name: Cole, Naida M, MD 
Authenticated: July 01, 2018 
 
Department Chair: Tsen, Lawrence C, MD 
Authenticated: July 02, 2018 
InitialReview  
 
Title: 
Second-line Uterotonics in Postpartum Hemorrhage: A Randomized Clinical Trial 
 
  
The Partners Human Research Committee has created several forms for review of human subjects research. 
This questionnaire includes a series of questions to identify the form (s) you need to complete for your 
research project.  
1.  Intervention/Interaction 
2.  Health / Medical Information 
3.  Excess Human Material and Related Health / Medical Information 
4.  Secondary Use of Research Samples and/or Data (samples/data from another research study) 
5.  Research Data Repository (collecting and storing health/medical information for future research) 
6.  Tissue or Sample Repository  
7.  Coordinating Center / Core Labs 
8.  Emergency / Single Patient Use of Investigational Products 
 
 
1. Intervention and/or Interaction 
  
Does your research involve an intervention and/or interaction with subjects for the collection of specimens 
or biological material or data (including health or clinical data, surveys, focus groups or observation or 
behavior)? 
  
NOTE: Do not answer YES if this protocol is to establish a Research Data Repository or 
Sample/Tissue  Repository. There are separate forms for Data and Tissue Repositories. 
 
◉  Yes  
 
⚪  No  
 
 
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Will the study population include children? 
 
⚪  Yes  
 
◉  No   
 
 
Will the study population include adults with impaired decision-making capacity for whom 
permission for participation will be obtained from their legally authorized representative (surrogate 
consent)? 
 
⚪  Yes  
 
◉  No   
 
 
Will the study population include neonates of uncertain viability and/or nonviable neonates? 
 
⚪  Yes  
 
◉  No   
 
 
Will the study population include pregnant women and/or fetuses? 
 
◉  Yes  
 
⚪  No  
 
 
 
Will the study population include any of the following: 
  Patients who are in the hospital at any time during the study (inpatients) 
  Patients seen in the Emergency Department 
  Patient Care Services Staff, e.g. nursing staff asked to complete surveys on patient care or 
nursing practice 
◉  Yes  
 
⚪  No  
 
 
 
Will you be doing either of the following: 
  Testing a drug, biologic, dietary supplement or other agent for safety and/or efficacy 
  Administering a drug, biologic, dietary supplement or other agent to study human 
physiology 
◉  Yes  
 
⚪  No  
 
 
 
Will you be doing any of the following: 
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  Testing a medical device for safety and/or efficacy 
  Using a marketed device in a non-standard (off-label) way 
  Using a commercially available device that is not approved for use in humans 
⚪  Yes  
 
◉  No   
 
 
Will the study involve ionizing radiation, e.g. x-ray, radioactive drug, fluoroscopy? 
 
⚪  Yes  
 
◉  No   
 
 
Will the study involve non-ionizing radiation, e.g. MRI, ultrasound, laser, ultraviolet light emitting 
device or microwave? 
 
⚪  Yes  
 
◉  No   
Sponsor Funding: Brigham and Women's Hospital - Internal Funds [Internal]  
 
Select the source of funding that will be used to support the proposed research: 
⚪  Government / Foundation / Other Non-Profit  
 
⚪  Corporate  
 
◉  Institutional Award  
 
⚪  Department Funds  
 
⚪  None   
 
Enter Peoplesoft fund # (if known): 
  
Insight Agreement proposal number (read-only field): 
2019A009692 
  
Enter Principal Investigator name (if different): 
Cole, Naida M 
 
  
Medicare Coverage Analysis Requirement 
  
Does the protocol for this study involve any items or services that will be billed to Medicare/private 
insurance, including study-specific procedures or those considered usual and customary care 
("standard of care") outside the trial context?  
⚪  Yes  
 
◉  No   
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NOTE: If you are unsure how to answer this question, please contact Sarah Bednar at Mass 
General Brigham Clinical Trials Office at 617-954-9364, or for NWH investigators, please 
contact Jayita Sen at 617-243-6517 for more information.  
  
 
Is this the primary source of funding? 
⚪  Yes  
 
⚪  No  
 
◉  Not applicable   
Sponsor Funding: None  
 
Select the source of funding that will be used to support the proposed research: 
⚪  Government / Foundation / Other Non-Profit  
 
⚪  Corporate  
 
⚪  Institutional Award  
 
⚪  Department Funds  
 
◉  None  
 
 
Is this the primary source of funding? 
⚪  Yes  
 
⚪  No  
 
◉  Not applicable   
Conflicts of Interest  
 
  
1. Is this study being funded or supported in whole or in part by an Outside Entity?  NOTE: Support 
includes providing funds, drug, device, or other resources.  Outside Entity means any corporation, 
foundation or other entity or organization that is not a Mass General Brigham entity including any 
governmental entity or non-profit. 
⚪  Yes  
 
◉  No  
 
 
  
2. Are you studying or are you using in any significant way a drug or device or other technology that is 
owned, developed or licensed by an Outside Entity?  NOTE: Technology that is used in a significant way 
includes, for example, imaging equipment that, while not the focus of the study, is an important part 
of the study design and will need to be described and identified in the methods section of a 
publication.  This includes licensed intellectual property such as patents, patent applications, and 
copyrighted materials, including technology licensed through Mass General Brigham. 
⚪  Yes  
 
◉  No  
 
Study Details  
 
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Study Classification  
  
The following information is being collected to allow the IRB to provide research administration with reports 
on the type of clinical research being conducted by Mass General Brigham investigators.  This is self-
reported information and will not affect what form questions you are presented with later in the 
application.  Please select all that apply. 
  
  
Type of Study: Select all that apply 
  
Intervention  
Therapeutic  
Content of Study: Select all that apply 
Pregnancy  
Surgery  
 
  
Will your research be limited to any of the following:   
  Collection of one or more blood samples.   
  Prospective collection of biological specimens for research purposes by noninvasive means.   
  Collection of data through noninvasive procedures (not involving general anesthesia or sedation) 
routinely employed in clinical practice.   
  Collection of data from voice, video, digital, or image recordings made for research purposes.   
  Research on individual or group characteristics or behavior or research employing survey, interview, 
oral history, focus group, program evaluation, human factors evaluation, or quality assurance 
methodologies.   
⚪  Yes  
 
◉  No  
 
  
NOTE: You must attach a detailed protocol on the attachments page of this submission using 
the Attachment Type 'Detailed Protocol.' 
 
  
Is this a randomized controlled clinical trial? 
⚪  Yes  
 
◉  No  
 
 
  
Does the research involve the use of human embryonic stem cells? 
⚪  Yes  
 
◉  No  
 
 
  
Does the research involve issues related to women's health? 
◉  Yes  
 
⚪  No  
 
 
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Is this a cancer-related trial? 
⚪  Yes  
 
◉  No  
 
 
NOTE: Cancer-related means the primary focus is cancer therapy OR the targeted population is only 
cancer patients (patients with diagnosed malignancy).  Most oncology / cancer-related research 
studies are reviewed by the DFCI IRB.  See the MGB IRB Oncology / Cancer Research 
Guidance BEFORE continuing with this IRB submission. 
 
  
Study Design 
  
Who designed the study? 
⚪  Cooperative Group / Consortium  
 
⚪  Corporate Sponsor  
 
◉  Mass General Brigham Investigator  
 
⚪  Other   
NOTE: When the corporate sponsor designs the study, the corporate sponsor's protocol must be 
submitted to the IRB for review. Before the research can begin, the IRB must approve the sponsor's 
protocol and Mass General Brigham Clinical Research Office must execute the Agreement with the 
sponsor. 
 
  
Will any data generated from this study be submitted to the FDA? 
⚪  Yes  
 
◉  No  
 
Clinical Trials Registration  
 
Clinical Trials Registration and Results Reporting 
 
Investigator–initiated clinical trials must be registered on ClinicalTrials.gov to comply with federal FDA 
requirements in FDA 42 CFR 11 (Final Rule) and/or NIH Policy. Studies that falls under both FDA and NIH 
requirements only need to be registered once. The information posted on ClinicalTrials.gov (CT.gov) must be 
updated and verified at least every 12 months. 
 
The following information is used to identify studies that require clinical trials registration and results 
reporting, and to inform Principal Investigators (PI) of their responsibilities for registration and results 
reporting. 
 
IMPORTANT NOTE: Even if your investigator-initiated clinical trial does not meet the NIH or FDA 
clinical trials registration requirements, you are strongly advised to read and consider registering 
your trial to comply with the following additional requirements: 
  A non-federal sponsor may require registration as part of the award's terms and conditions 
  International Committee of Medical Journal Editors (ICMJE) for publication purposes  
  Center for Medicare & Medicaid for research billing claims for qualifying clinical trials (Mass 
General Brigham Clinical Trials Office will notify you if applicable)  
  Research funders now requiring registration and results reporting: May 18, 2017 Joint 
Statement 
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For additional information, please see the Human Research Affairs Compliance and Education Office 
website for Clinical Trials Registration. 
  
 
  
Is this a Mass General Brigham investigator – initiated research study? 
 
⚪  No  
 
◉  Yes  
 
 
 
Is this research funded in whole or in part by NIH AND does this research meet the NIH's definition of 
clinical trial? 
 
NIH defines a clinical trial as any research study that meets all of the following criteria: 
  The study involves human participants;  
  The participants are prospectively assigned to an intervention;  
  The study is designed to evaluate the effect of the intervention on participants; AND 
  The effect being evaluated is a health-related, biomedical or behavioral outcome. 
 
◉  No   
⚪  Yes  
 
 
 
Is the study an interventional clinical trial? 
 
In the FDA Final Rule with respect to a clinical study or clinical investigation, 
  Interventional is defined to mean that participants are assigned prospectively to an 
intervention or interventions according to a protocol to evaluate the effect of the 
intervention(s) on biomedical or other health-related outcomes. [Source: 42 CFR 11.10(a); 
81 FR 65140-41] 
  Clinical Trial is defined as a clinical investigation or a clinical study in which human 
subject(s) are prospectively assigned, according to a protocol, to one or more interventions 
(or no interventions) to evaluate the effect(s) of the intervention(s) on biomedical or health-
related outcomes. [Source: 42 CFR 11.10(a); 81 FR 65139] 
⚪  No  
 
◉  Yes  
 
 
  
Does this research evaluate at least one drug, biological or device product regulated by the 
United States Food and Drug Administration (U.S. FDA)? 
  FDA regulated includes both approved and investigational drugs, biologics and 
device. 
  A device product regulated by FDA, includes significant risk devices for which 
approval of an IDE is required by FDA, non-significant risk devices that are considered 
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to have an approved IDE in accordance with 21 CFR 812.2(b), or device products that 
are exempt from the submission requirements of 21 CFR part 812. [Source: 81 FR 
65012] 
  A drug product regulated by the FDA includes a drug that is the subject of an 
approved NDA [new drug application] or BLA [biologic license application] or that 
would require an approved NDA or BLA to be legally marketed in the United States. A 
non-prescription drug product that is or could be marketed under an existing over-the-
counter drug monograph is not considered an Applicable Clinical Trial (ACT). [Source: 
81 FR 65041] 
⚪  No  
 
◉  Yes  
 
 
  
Is the study other than a phase 1 trial of a drug and/or biological product or is the study 
other than a device feasibility study? 
  Study phase means, for a clinical trial of a drug product (including a biological 
product), the numerical phase of such clinical trial, consistent with terminology in 
21 CFR 312.21, such as phase 2 or phase 3, and in 21 CFR 312.85 for phase 4 
studies. [Source: 42 CFR 11.10(b)(6); 71 FR 65141] 
  Device feasibility means a device is being evaluated for the feasibility of the 
product or of a test prototype device and not health outcomes. [Source: 81 FR 
65035] 
◉  Yes    
⚪  No    
 
 
Do ANY of the following apply?  Answer YES if the answer to at least ONE of the 
following three questions is YES. 
  Is at least one study facility located in the United States or a U.S. territory? 
  Is the study conducted under a U.S. FDA Investigational New Drug 
application or Investigational Device Exemption? 
  Does the study involve a drug, biological, or device product that is 
manufactured in and exported from the U.S. (or a U.S. territory) for study in 
another country?  
⚪  No  
 
◉  Yes  
 
  
The responses to the questions above indicate this study meets the FDA 
Final Rule requirements for clinical trials registration. Mass General 
Brigham Institutions have delegated responsibility for clinical trials 
registration, periodic updates, and results and adverse event reporting to 
the Principal Investigator ('Responsible Party'). This study must be 
registered on ClinicalTrials.gov prior to the first subject being enrolled 
into the study.   
 
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Responsible Party 
 
Enter Name of MGB investigator who will be the Responsible Party, for 
example, Jane Doe, MD: 
  
Jimin Kim, MD 
 
Enter the full name of the MGB Institution of the MGB investigator, for example, 
Massachusetts General Hospital: 
  
Brigham and Women's Hospital 
 
 
Documentation of ClinicalTrials.gov Registration 
 
Have you submitted registration information to ClinicalTrials.gov? 
 
⚪  No  
 
◉  Yes  
 
 
Indicate if a National Clinical Trial (NCT) registration number has been 
assigned: 
 
◉  Assigned  
 
⚪  Pending  
 
 
Enter the NCT number; for example NCT12345678: 
 
NCT03584854 
 
 
Results Reporting 
 
ClinicalTrials.gov results reporting is required within 12 months of the 
primary endpoint completion date defined as the date that the final 
subject was examined or received the intervention for the purposes of 
collection of primary outcome. Early consultation is strongly advised. 
Please contact the QI Program for assistance: 
 
Mass General Brigham Human Research Quality Improvement (QI) 
Program: humanresearchqi@partners.org 
 
Additional information can be found at: 
QI Program website 
www.ClinicalTrials.gov 
Study Population  
 
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How many subjects do you plan to enroll at Mass General Brigham' sites? 
950 
NOTE: Target enrollment at Mass General Brigham sites is the number of subjects you expect to 
provide written or verbal consent, or implied consent by voluntary completion of a survey or 
participation in a focus group. 
 
How many subjects will be enrolled study-wide? 
1250 
 
What is the age range of eligible subjects who will be enrolled at Mass General Brigham sites?   
  
Enter 'None' if there is no maximum age. 
Minimum age: 
18 
Maximum age: 
50 
 
Equitable Selection of Subjects 
 
Will both males and females be enrolled? 
⚪  Yes  
 
◉  No  
 
 
Which gender will be enrolled? 
◉  Females only  
 
⚪  Males only  
 
 
Indicate below whether the study population that is being targeted for the research is any of the following 
groups that require additional protections: 
☐  Children (less than 18 years of age) 
☐  Economically or Educationally Disadvantaged 
☐  Embryos 
☐  Employees under the direct supervision of the investigators conducting the research 
☐  Employees (physician, nurses, or other healthcare workers) in the course of, or related to, their 
employment related duties 
☐  Individuals with Impaired Decision-Making Capacity 
☐  Neonates -age up to 28 days 
☐  Non-English Speakers 
☐  Patients from the Medical Practice of the Investigator 
☑  Pregnant Women / Fetuses 
☐  Prisoners 
☐  Students of Harvard Medical School 
☐  U.S. Military Personnel 
☐  None of the above 
Performance Sites / Facilities  
Where will investigators covered by this IRB consent/enroll subjects and perform study procedures?   
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☑  BWH 
BWH facilities/resources. Check all that 
apply. 
☐  Emergency Department 
☐  Clinical Trials Center 
☐  Health Centers 
☐  Inpatient 
☑  Labor & Delivery / Post Partum 
Floors 
☐  NICU 
☑  Operating Room / Recovery Room 
☐  Outpatient 
 
☐  Faulkner 
 
☐  MEE 
 
☐  MGH 
 
☐  NSMC 
 
☐  NWH 
 
☐  PCHI 
 
☐  Shriners 
 
☐  SRH 
 
☐  IHP 
 
☐  McLean 
 
☐  Broad Institute 
 
☐  Network Sites (e.g. NeuroNEXT and Stride) 
 
☐  Off-site Research (off-site means sites other than those owned or controlled by Mass General 
Brigham entities) 
  
NOTE: When more than one Mass General Brigham site is included in the submission, designate a 
Site-Responsible Investigator (not Residents, Fellows, or Trainees) for each site on the Staff & 
Access page. 
 
Is this a Mass General Brigham investigator-initiated multi-site study? 
◉  Yes  
 
⚪  No  
 
 
Enter the name of each of the institutions/entities where informed consent will be obtained and where 
study procedures will be performed by investigators who are not affiliated with Mass General Brigham 
System. 
Northwestern Memorial Hospital  
Enter the Institution Federal Wide Assurance number (FWA), if applicable: 
FWA00001550 
NOTE: A list of OHRP-approved assurances (FWA) is available on the OHRP website. 
  
Enter the IRB Contact for the Institution: 
Heather Yates, IRB coordinator; heather.yates@northwestern.edu 
Enter the IRB contact phone number: 
678-983-8964 
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NOTE: Investigators who are not affiliated with Mass General Brigham System must obtain IRB 
approval from their own institution. These investigators should not be listed on the Staff & 
Access page.  Each non-affiliated performance site must submit documentation of local IRB 
approval to the Mass General Brigham PI prior to initiation of the research at that site.  Attach or 
forward copies of IRB approval to the MGB IRB when received from the performance site(s). 
Recruitment  
 
 
Source of Subjects 
  
Indicate whether you will use any of the following resources to identify prospective subjects: 
☐  Census / Public Records 
☐  Commercial Mailing Lists 
☐  Emergency Department 
☐  Inpatient Units 
☑  Medical Records 
☑  Outpatient Clinics 
☑  Primary Physician / Physician Specialist 
☐  Registries / Patient Databases (e.g. cancer registry) 
☐  Research Patient Data Registry (RPDR) 
☐  Research Match (Vanderbilt Recruitment Tool) 
☐  RSVP for Health 
☐  Research Studies 
☐  None of the above 
 
Note: For more information about ResearchMatch, see https://www.researchmatch.org/about/ 
  
 
  
Methods / Materials 
  
Indicate whether you will use any of the following methods / materials to recruit subjects: 
☐  Advertisements - E-Mail 
☐  Advertisements - Internet 
☐  Advertisements - Rally https://rally.partners.org (Contact rallyforresearch@partners.org for more 
information) 
☐  Advertisements - Newspaper (e.g. Metro, Boston Globe) 
☐  Advertisements - Radio 
☐  Advertisements - Television 
☑  Flyers / Postings (e.g. within BWH or MGH) 
☐  Patient Gateway - Personalized Letters 
☐  Patient Gateway - Targeted Research Announcements 
☐  Mail 
☐  ResearchMatch Volunteer Message (see https://www.researchmatch.org/researchers/) 
☐  Telephone Calls to Prospective Subjects (who have previously agreed to be contacted, e.g. RSVP 
for Health) 
☐  None of the above 
  
NOTES: 
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1.  The text of all advertisements, letters, and telephone calls/scripts used to recruit subjects 
must be submitted for IRB approval.  You may attach these documents to the application on 
the Attachments page.  For guidance on recruitment and advertising, please see the following 
MGB IRB web pages Recruitment of Research Subjects and Guidelines for Advertisements 
for Recruiting Subjects. 
2.  When using Research Match, you must submit the contact message template for Research 
Match advertisement to the IRB for approval.  The contact message template is available to 
registered researchers on the ResearchMatch website. 
 
  
Pre-Screen of Subjects During Recruitment 
 
Will you ask prospective subjects pre-screening questions over the phone to determine eligibility? 
⚪  Yes  
 
◉  No  
 
 
 
Will you ask prospective subjects to complete an online pre-screening tool to determine eligibility? 
◉  Yes  
 
⚪  No  
 
 
Note: Refer to Mass General Brigham Guidance on Pre-Screening of Subjects During Recruitment.  
Remuneration  
 
Will subjects be paid or receive any type of remuneration / compensation for their time and expenses? 
⚪  Yes  
 
◉  No  
 
Informed Consent  
  
For guidance, refer to the MGB IRB web page Informed Consent of Research Subjects. 
  
 
Will informed consent and authorization for participation in research be obtained verbally (oral consent), or 
by use of a written consent form approved by the MGB IRB and signed by the subject or the subject's 
legally authorized representative? 
◉  Yes  
 
⚪  No  
 
  
Indicate how informed consent and authorization will be obtained: 
◉  Written  
 
⚪  Verbal (oral consent)  
 
 
  
Enter the description of the study population (as listed on page 1 of the informed consent) for each 
consent form. 
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Pregnant patients age 18-50 undergoing non-emergent cesarean section at BWH  
 
Indicate who will obtain the informed consent of the subject or the subject's legally authorized 
representative. 
☑  Licensed Physician Investigator 
☐  Non-Physician Investigator 
☐  Other 
 
Indicate from whom informed consent will be obtained. Check all that apply: 
☑  Adult Subject 
☐  Parent(s) / Guardian for Child 
☐  Court-Appointed Guardian for Adult 
☐  Surrogate for Adult, other than Guardian (e.g. health care proxy, person with durable power of 
attorney, spouse, adult child, or close family member). 
NOTE: When surrogate consent for adults is obtained, the individuals with impaired decision-
making capacity form must be completed.  For guidance, refer to the following MGB IRB web 
pages, Surrogate Consent to Research for Individuals with Impaired Decision-making Capacity 
 
Will the research target a non-English speaking group? 
⚪  Yes  
 
◉  No   
  
NOTE: When investigators can reasonably expect that more than an incidental number of 
subjects speaking the same non-English language will be enrolled (for example, if the research 
is targeting a non-English speaking group), the use of a written translation of the entire English 
version of the consent form is required.  The MGB IRB must approve all written translated 
versions of the consent from and recommends that the written translation be done by an in-
house medical translator from Interpreter Services or other qualified person or service 
recommended by Interpreter Services. Refer to the MGB IRB guidance on Obtaining And 
Documenting Informed Consent Of Subjects Who Do Not Speak English. 
  
 
Will a study subject advocate participate in the consent process? 
⚪  Yes  
 
◉  No   
NOTE: A study subject advocate may be used, for example, because subjects have limited time 
to consider participation in a study involving significant risk, or may feel obligated to participate. 
 
Will subjects have less than 12 hours to decide whether or not to participate? 
⚪  Yes  
 
◉  No   
  
NOTE: The IRB may waive the requirement to obtain a signed written consent / authorization form if it 
finds either: (1) the only record linking the subject and the research is the consent form and the 
principal risk would be potential harm resulting from a breach in confidentiality; or (2) the research 
presents no more than minimal risk of harm to subjects and involves no procedures for which 
written consent is normally required outside the research context. 
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Diaries  
 
Will subjects be asked to complete a diary(ies)?  For example, a drug diary, pain diary, symptom diary, etc. 
⚪  Yes  
 
◉  No  
 
Privacy / Confidentiality  
 
 
Health/Medical Records 
 
Will medical history / clinical information be obtained from the subject's health / medical record for study 
purposes? 
 
◉  Yes  
 
⚪  No  
 
 
Explain what information will be abstracted from health / medical records: 
 
Basic patient demographic information, pertinent medical history, details of their pregnancy, labor 
and delivery, peripartum laboratory values and postpartum outcomes will be abstracted and 
recorded. 
 
 
Will sensitive personal health information resulting from this study become part of the subject's 
health/medical record?  
 
⚪  Yes  
 
◉  No  
 
  
Sensitive personal information obtained for research purposes typically does not become part of the 
subject’s health/medical record.  Rather, these data are retained in the research records only. 
  
NOTE: Certain categories of medical information are commonly recognized as potentially sensitive, 
such as information related to mental health; sexual behaviors or sexual orientation; illegal 
behaviors; and substance abuse.  Some genetic test results may be viewed similarly.  When 
applicable, investigators are reminded to inform subjects in the consent form that sensitive personal 
health information may become part of their health/medical record, e.g., routine testing for HIV 
infection. 
 
 
Will you enroll subjects in the study in Epic? 
 
⚪  Yes  
 
◉  No  
 
 
NOTE: Epic is both the Mass General Brigham electronic medical record and the billing system, 
including research billing. For more information about Epic/eCare, refer to Research Information 
Services & Computing's Support & Training page eCare Research FAQs. 
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Do you consider this to be a sensitive study that requires the title of the study be masked in the electronic 
medical record (eCare)? 
 
⚪  Yes  
 
◉  No  
 
 
NOTE: The title of studies determined to be sensitive will be masked in the Mass General Brigham 
eCare system (e.g., Psychiatry Study 1 will appear as MGB 2017P001234).  The IRB is responsible for 
making the final determination whether a study is sensitive.  Examples of studies that may be 
considered sensitive are studies that collect information about:  
  sexual practice 
  sexual victimization 
  illegal behaviors 
  alcohol, drugs, or other addictive products 
  stigmatizing illnesses 
 
 
Certificate of Confidentiality 
 
NIH funded research that collects or uses identifiable sensitive information is automatically issued a 
Certificate of Confidentiality as part of the terms and conditions of the award. The NIH considers research 
that is reviewed by the IRB to involve identifiable sensitive information requiring a Certificate. 
 
If you do NOT have NIH funding, do you have or do you plan to obtain a Certificate of Confidentiality to 
protect the data from disclosure (e.g., by court order or subpoena)? 
 
 
 
⚪  Yes  
 
◉  No  
 
 
NOTE: For information on Certificates of Confidentiality, refer to the OHRP website. 
 
 
Sending Health Information to Research Collaborators Outside Mass General Brigham 
 
 
Will identifiable information be shared with research collaborators outside Mass General Brigham? 
 
⚪  Yes  
 
◉  No  
 
 
NOTE: Data that includes any of the identifiers listed below are considered identifiable. 
 
  Names, including initials  
  Social security numbers  
  Medical record numbers  
  Addresses by street location  
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  Addresses by city, county, precinct, zip code  
  All elements of dates (except year) related directly to individuals including, but not limited to, 
dates of birth, death, admission, discharge, or any service  
  All ages over 89 and all elements of dates (including year) indicative of such age  
  Telephone numbers  
  FAX numbers  
  Electronic email addresses  
  Web URLs  
  Internet protocol (IP) addresses  
  Account numbers  
  Certificate/license numbers  
  Vehicle identification numbers and serial numbers including license plates  
  Medical device identifiers and serial numbers  
  Biometric identifiers, including finger and voice prints  
  Full face photographs and any other comparable images  
  Any other unique identifying numbers, characteristics or codes including, but not limited to, 
globally unique identifiers (GUID) and universally unique identifiers (UUID) or equivalent 
 
For guidance, refer to the MGB IRB web page on the HIPAA Privacy Rule. 
  
 
  
 
NOTE: Non-institutional email services are not approved to transmit confidential data.  Use “Send 
Secure” to transmit confidential data to non-institutional email domains (e.g., gmail, yahoo, icloud, 
etc.).  For more information on appropriate methods of transmitting research information/data to 
research collaborators, refer to the Research Information & Computing website. 
 
 
Business Associates 
 
Will identifiable information be shared with persons or entities outside of Mass General Brigham who are not 
research collaborators or who are not part of the research team, but who will perform some aspect of the 
research on behalf of Mass General Brigham, e.g., a private recruitment agency, outside laboratory or data 
analysis group? 
 
⚪  Yes  
 
◉  No  
 
 
NOTE: In this situation, the persons or entities referred to above are considered business associates 
of Mass General Brigham, therefore a Business Associate Agreement is required. 
Instruments / Questionnaires  
 
  
Will the research involve the development of instruments, questionnaires, surveys, interviews, and/or focus 
group topics? 
⚪  Yes  
 
◉  No  
 
 
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Will the research involve the use of instruments, questionnaires, surveys, interviews, and/or focus group 
topics? 
⚪  Yes  
 
◉  No  
 
Ancillary Drugs  
 
Will you be using FDA-approved drugs for research-related ancillary/supportive care? 
⚪  Yes  
 
◉  No  
 
 
NOTE:  An ancillary drug is a commercially available drug that is being used for a research-related 
ancillary test or for supportive care (e.g. methacholine challenge tests, lidocaine for research-related 
biopsies, EMLA cream for venipuncture, contrast agent for scans or x-rays).  The Research Consent 
Form should include the risks of ancillary drugs being administered as part of the research. 
Ancillary Devices  
 
Will any non-hospital inventory FDA-approved medical devices be used to obtain measurements, collect 
data, or monitor subjects?   
⚪  Yes  
 
◉  No  
 
  
NOTE: When the sponsor (or another party) provides a medical device for use to obtain 
measurements, collect data, or monitor subjects, the investigator must request a zero dollar 
purchase order to track receipt of the medical device and to document BME inspection for electrical 
safety, when necessary. For more information, refer to the Zero Dollar Purchase Order Policy. 
Non-Intervention / Non-Interaction Group  
In addition to the intervention/interaction group that provides informed consent to participate in the research, 
do you plan to also review the health/medical records or other private/confidential information of any subjects 
with whom you will have no contact at any time?  
⚪  Yes  
 
◉  No  
 
Pregnant Women or Human Fetuses  
 
Federal regulations require the IRB to provide additional protections for pregnant women and human fetuses 
involved in research [45 CFR 46.204].   
  
Assessing Risks And Benefits 
When assessing risks and benefits, consider the variability in health status of the subjects to be enrolled, 
their medical experiences, and the extent to which the research procedures will be a burden to the subjects 
in the context of their daily lives and/or routine medical care.  Procedures that usually present no more than 
minimal risk include: urinalysis, obtaining a small amount of blood, EEGs, allergy scratch tests, minor 
changes in diet or daily routine, and/or the use of standard psychological or educational tests.  The 
assessment of the probability and magnitude of the risk, however, may vary depending on the diseases or 
conditions the subjects may have. 
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Minimal Risk 
As defined in the regulations 45 CFR 46.102(i), “minimal risk means the probability and magnitude of harm 
or discomfort anticipated in the research are not greater in and of themselves than those ordinarily 
encountered in daily life or during the performance of routine physical or psychological examinations or 
tests.”   
  
 
Pregnant women or fetuses may be involved in research if all of the following conditions listed below are met 
[45 CFR 46.204].  Please provide study-specific information with your explanations. 
  
(a) Where scientifically appropriate, pre-clinical studies, including studies on pregnant animals, and clinical 
studies (including studies on non-pregnant women) have been conducted and provide data for assessing 
potential risks to pregnant women and fetuses. 
  
Provide a brief description of relevant prior pre-clinical and clinical studies, and based on this information, 
what you think the risks to pregnant women and to the fetus are in your research.  
This study will prospectively evaluate the clinical efficacy of methylergonovine compared to carboprost. 
The two agents are used as second-line uterotonics in the case of atonic postpartum hemorrhage (PPH) 
refractory to oxytocin, but it is unclear which is the more effective drug for this indication. One recent 
observational study suggests that methylergonovine may be superior to carboprost in reducing PPH-
related morbidity, although residual confounding may be responsible for this finding. [Butwick et al. Am J 
Obstet Gynecol 2015] There are no randomized trials comparing clinical outcomes of methylergonovine 
vs carboprost in PPH to date.  
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. Given this, we believe there will be no added risk to pregnant women experiencing 
atonic PPH by receiving methylergonovine or carboprost in a randomized manner. 
  
(b) The risk to the fetus is caused solely by the interventions or procedures that hold out the prospect of 
direct benefit for the woman or the fetus; if there is no such prospect of direct benefit, the risk to the fetus is 
not greater than minimal and the purpose of the research is the development of important biomedical 
knowledge which cannot be obtained by other means. 
  
Does the research hold out the prospect of direct benefit for the woman, or to the fetus? 
◉  Yes  
 
⚪  No  
 
Explain what direct benefit may accrue to the women taking part in this research, or to the fetuses. 
Treatment with second-line uterotonics (methylergonovine or carboprost) has the potential to save 
a mother's life in cases of severe postpartum hemorrhage (PPH). Both of these drugs will be 
available to all study participants, but the order in which they are eligible to receive either drug will 
be randomized. They will receive one or both medications in a timely manner to stop bleeding. Any 
additional interventions will be offered as per usual standard of care at our hospital. 
  
(c) Any risk is the least possible for achieving the objectives of the research. 
  
Explain how the risks have been minimized to the least possible to achieve the research objectives.   
Patients will be given information about the study prior to their admission, as well as at the time of 
consent for participation. They will have the opportunity to ask questions and clarify the details 
regarding participation in the study. Patients will be given a written consent form to sign, which will list 
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all possible risks of study participation. A physician investigator will be present at all times during the 
consent process, enrollment and conduct of the study.  
Patients will receive standard care in all aspects except the order in which they receive two clinically 
equivalent 2nd-line uterotonics. If at any time a patient wishes to withdraw from the study, they may do 
so voluntarily. The principal investigator will review study records after every 5 new patients enrolled. 
The principal investigator will take full responsibility for standardized review of recruitment at the above 
frequency, to ensure adherence to protocol, detection of minor or major adverse events (AEs), and 
timely reporting of such events to the IRB with halting of the study if necessary (for any AEs). 
 
Informed Consent  
Check all that apply:   
☑  Informed consent will be obtained from the pregnant woman in accordance with the consent 
provisions of Federal regulation 45 CFR 46.116. 
☐  When the research holds out the prospect of direct benefit solely to the fetus, informed consent 
will be obtained from the father in accordance with the consent provisions of 45 CFR 46.116, 
except, if he is unable to consent because of unavailability, incompetence, or temporary incapacity, 
or the pregnancy resulted from rape or incest. 
☑  Each individual providing consent will be fully informed regarding the reasonably foreseeable 
impact of the research on the fetus. This information is included in the Mass General Brigham 
Research Consent Form. 
 
MASSACHUSETTS GENERAL LAW CHAPTER 112, SECTION 12J   
  
Experimentation on human fetuses prohibited; medical procedures authorized; consent; approval; civil and 
criminal liability and proceedings; severability.    
  
(a)I. No person shall use any live human fetus whether before or after expulsion from its mother's womb for 
scientific, laboratory, research or other kind of experimentation. This section shall not prohibit procedures 
incident to the study of a human fetus while it is in its mother's womb, provided that in the best medical 
judgment of the physician, made at the time of the study, said procedures do not substantially jeopardize the 
life or health of the fetus, and provided said fetus is not the subject of a planned abortion. 
(a)II. No experimentation may knowingly be performed upon a dead fetus unless the consent of the mother 
has first been obtained, provided, however, that such consent shall not be required in the case of a routine 
pathological study. 
(a)III. No person shall perform or offer to perform an abortion where part or all of the consideration for said 
performance is that the fetal remains may be used for experimentation or other kind of research or study.   
Nursing Implementation and Planning  
 
Emergency Department / Inpatient Research 
  
Will subjects be recruited from the Emergency Department or be inpatients while on study? 
⚪  Yes  
 
◉  No  
 
 
  
Patient Care / Nursing Practice Research 
  
Will nursing staff be asked to complete surveys on patient care or nursing practices? 
⚪  Yes  
 
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◉  No  
 
Drugs / Biologics / Dietary Supplements: Carboprost Tromethamine  
NOTE:  Do not complete this form for FDA-approved drugs administered for ancillary tests / 
supportive care, e.g. methacholine challenge tests, lidocaine for research-related biopsies, contrast 
agents. 
 
Manufacturer Information 
Name: 
PHARMACIA UPJOHN, CO 
 
  
Type of Agent 
  
Select: 
◉  Drug  
 
⚪  Biologic  
 
⚪  Dietary Supplement  
 
⚪  Stable Isotope    
 
FDA Status of Drug 
  
Select: 
◉  Marketed Drug (FDA-approved for sale by prescription or over-the-counter)   
⚪  Not Marketed Drug (Not FDA-approved for sale by prescription or over-the-counter)  
 
 
 Indication for Use of Drug 
  
Select: 
◉  The drug will be used for an indication in the approved labeling  
 
⚪  The drug will be used for a non-approved indication (off-label)   
 
Explain the indication for use of drug in this study:  
Carboprost is used for the treatment of postpartum hemorrhage due to atony that is 
refractory to oxytocin. 
 
  
Is the drug a Schedule II narcotic? 
⚪  Yes  
 
◉  No  
 
  
NOTE: For a list of Schedule drugs, refer to the US Department of Justice web page. 
 
  
Investigational New Drug 
  
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Will this agent be studied under an IND? 
⚪  Yes  
 
◉  No  
 
 
  
Study Phase / Design 
  
Select the study phase (if applicable): 
⚪  Phase 1  
 
⚪  Phase I / II  
 
⚪  Phase II  
 
⚪  Phase II / III  
 
⚪  Phase III  
 
⚪  Phase III / IV  
 
◉  Phase IV  
 
⚪  Pilot  
 
⚪  Treatment IND   
  
Indicate the study design: 
☑  Randomized 
☐  Single Blind 
☑  Double Blind 
☐  Open Label 
☐  Placebo-Controlled 
☐  Multi-Center 
☐  Cross Over 
☐  Dose-Finding 
 
  
Agent Formulation 
  
Do you know how the drug is packaged and what form it is in? 
◉  Yes  
 
⚪  No  
 
 
  
Enter the number of units, for example for 50 mg, type '50' 
250  
  
Select the form of the agent: 
Ampoule  
  
Select the agent units: 
mcg  
 
  
Agent Dispensing 
  
Indicate where the agent will be housed and dispensed: 
☐  Faulkner Pharmacy 
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☐  MGH Research Pharmacy 
☐  McLean Pharmacy 
☐  NSMC Pharmacy 
☐  NWH Pharmacy 
☐  SRH Pharmacy 
☐  MEE Pharmacy 
☑  Other 
Specify where the agent will be housed and dispensed: 
The agents are kept as standard 'emergency' medications in the omnicell directly outside the 
operating rooms on the L&D floor at BWH. Each study drug (as determined by randomization) will 
be accessed directly from this omnicell by the anesthesiologist (or a non-study member of the 
anesthesia team taking care of the patient) at the time of obstetrician's request for a second-line 
uterotonic. It will be labelled, dispensed and documented in the chart in usual fashion (unblinded) 
by the anesthesiologist. The anesthesiologist will not reveal the identity of the drug to the rest of 
the O.R. team. 
☐  BWH Investigational Drug Service 
 
  
Agent Preparation 
  
Will the Research Pharmacy be responsible for preparation of the dose? 
⚪  Yes  
 
◉  No  
 
 
  
Agent Storage Requirements (following shipment) 
  
Check all that apply: 
☐  Room Temperature 
☐  Stored in locked vault or cabinet 
☑  Refrigerator (36 - 46F or 2-8C) 
☐  -20C Freezer 
☐  -40 C Freezer (available at BWH only) 
☐  -80C Freezer 
☐  Other 
  
NOTE: For studies involving the use of drugs and/or biologics, the following must be submitted for 
the IRB review: investigational drug brochure or equivalent information, product information 
(package insert or equivalent on marketed products). These documents may be attached in the 
"Attachments" section of this application.   
Drugs / Biologics / Dietary Supplements: Methylergonovine  
NOTE:  Do not complete this form for FDA-approved drugs administered for ancillary tests / 
supportive care, e.g. methacholine challenge tests, lidocaine for research-related biopsies, contrast 
agents. 
 
Manufacturer Information 
Name: 
NOVARTIS 
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Type of Agent 
  
Select: 
◉  Drug  
 
⚪  Biologic  
 
⚪  Dietary Supplement  
 
⚪  Stable Isotope    
 
FDA Status of Drug 
  
Select: 
◉  Marketed Drug (FDA-approved for sale by prescription or over-the-counter)   
⚪  Not Marketed Drug (Not FDA-approved for sale by prescription or over-the-counter)  
 
 
 Indication for Use of Drug 
  
Select: 
◉  The drug will be used for an indication in the approved labeling  
 
⚪  The drug will be used for a non-approved indication (off-label)   
 
Explain the indication for use of drug in this study:  
Methylergonovine is used for the treatment of postpartum hemorrhage due to atony that 
is refractory to oxytocin. 
 
  
Is the drug a Schedule II narcotic? 
⚪  Yes  
 
◉  No  
 
  
NOTE: For a list of Schedule drugs, refer to the US Department of Justice web page. 
 
  
Investigational New Drug 
  
Will this agent be studied under an IND? 
⚪  Yes  
 
◉  No  
 
 
  
Study Phase / Design 
  
Select the study phase (if applicable): 
⚪  Phase 1  
 
⚪  Phase I / II  
 
⚪  Phase II  
 
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⚪  Phase II / III  
 
⚪  Phase III  
 
⚪  Phase III / IV  
 
◉  Phase IV  
 
⚪  Pilot  
 
⚪  Treatment IND   
  
Indicate the study design: 
☑  Randomized 
☐  Single Blind 
☑  Double Blind 
☐  Open Label 
☐  Placebo-Controlled 
☐  Multi-Center 
☐  Cross Over 
☐  Dose-Finding 
 
  
Agent Formulation 
  
Do you know how the drug is packaged and what form it is in? 
◉  Yes  
 
⚪  No  
 
 
  
Enter the number of units, for example for 50 mg, type '50' 
0.2  
  
Select the form of the agent: 
Vial  
  
Select the agent units: 
mg  
 
  
Agent Dispensing 
  
Indicate where the agent will be housed and dispensed: 
☐  Faulkner Pharmacy 
☐  MGH Research Pharmacy 
☐  McLean Pharmacy 
☐  NSMC Pharmacy 
☐  NWH Pharmacy 
☐  SRH Pharmacy 
☐  MEE Pharmacy 
☑  Other 
Specify where the agent will be housed and dispensed: 
The agents are kept as standard 'emergency' medications in the omnicell directly outside the 
operating rooms on the L&D floor at BWH. Each study drug (as determined by randomization) will 
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be accessed directly from this omnicell by the anesthesiologist (or a non-study member of the 
anesthesia team taking care of the patient) at the time of obstetrician's request for a second-line 
uterotonic. It will be labelled, dispensed and documented in the chart in usual fashion (unblinded) 
by the anesthesiologist. The anesthesiologist will not reveal the identity of the drug to the rest of 
the O.R. team. 
☐  BWH Investigational Drug Service 
 
  
Agent Preparation 
  
Will the Research Pharmacy be responsible for preparation of the dose? 
⚪  Yes  
 
◉  No  
 
 
  
Agent Storage Requirements (following shipment) 
  
Check all that apply: 
☐  Room Temperature 
☐  Stored in locked vault or cabinet 
☑  Refrigerator (36 - 46F or 2-8C) 
☐  -20C Freezer 
☐  -40 C Freezer (available at BWH only) 
☐  -80C Freezer 
☐  Other 
  
NOTE: For studies involving the use of drugs and/or biologics, the following must be submitted for 
the IRB review: investigational drug brochure or equivalent information, product information 
(package insert or equivalent on marketed products). These documents may be attached in the 
"Attachments" section of this application.   
Attachments 
 
Name 
Mode 
8.17.2021 Consent Form - CLEAN  
Electronic  
04.19.22 Methergine Hemabate IRB Detailed Protocol--CLEAN 
(Detailed Protocol)  
Electronic  
Second-Line Uterotonics- Data Collection Sheet (Data Collection 
Form)  
Electronic  
Uterine Tone Score Intraop Data Collection_4.29.19 (Data 
Collection Form)  
Electronic  
8.17.2021 Flier- CLEAN (Flyer)  
Electronic  
8.17.2021 18-24 Hour Interview Guide- CLEAN 
(Instrument/Questionnaire)  
Electronic  
8.17.2021 2-4 Hour Interview Guide - CLEAN 
(Instrument/Questionnaire)  
Electronic  
Continuing Review Adverse Event Attestation (Other)  
Electronic  
Correspondence_for_STU00214439 (Other)  
Electronic  
Methergine Package Insert (Package Insert)  
Electronic  
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Name 
Mode 
Hemabate Package Insert (Package Insert)  
Electronic  
04.19.22 Protocol Summary-CLEAN (Protocol Summary)  
Electronic  
8.17.2021 Email to Patients- Uterotonics Study CLEAN 
(Recruitment Letter)  
Electronic  
Page 28 of 99

Partners HealthCare System
Research Consent Form
General Template
Version Date:  August 2016
Page 1 of 11
Subject Identification
Protocol Title: Second-Line Uterotonics in Postpartum Hemorrhage: A 
Randomized Clinical Trial
Principal Investigator: Jimin Kim, MD
Site Principal Investigator: Jimin Kim, MD
Description of Subject Population: Pregnant women undergoing non-emergent 
cesarean section delivery at BWH
About this consent form
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form.
Partners HealthCare System is made up of Partners hospitals, health care providers, and 
researchers.  In the rest of this consent form, we refer to the Partners system simply as 
“Partners.”
If you have any questions about the research or about this form, please ask us.  Taking part in 
this research study is up to you.  If you decide to take part in this research study, you must sign 
this form to show that you want to take part.  We will give you a signed copy of this form to 
keep.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time.
Why is this research study being done?
The purpose of this study is to compare how well 2 FDA-approved drugs, methylergonovine and 
carboprost, work to stop excessive bleeding after delivery. Most of the time when women have 
too much bleeding after delivery, it is because the uterus does not contract effectively. Currently, 
if there is too much bleeding after delivery, we use either one of these drugs to stop the bleeding, 
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Partners HealthCare System
Research Consent Form
General Template
Version Date:  August 2016
Page 2 of 11
Subject Identification
but it is not known which drug is better. The decision to use one drug or the other is based on 
physician’s preferences and institutional customs, since there are no national or international 
guidelines recommending the use of one over the other. 
We are asking you to take part in this study because you are going to have a cesarean section 
delivery. Patients who have this surgery may have too much bleeding right afterwards, and we 
would like to find out what is the best drug to treat this bleeding, if it happens.
About 100 patients will take part in this study.
How long will I take part in this research study?
You will be involved in the study during the time of your cesarean section from the time your 
baby is born until the end of the surgery.
What will happen in this research study?
If you appear to be eligible and are interested in participating, we will explain the study to you 
once you are in hospital and preparing for your cesarean section. If you choose to take part in 
this study, we will ask you to sign this consent form. 
When you have your baby in the operating room, you will receive a drug called oxytocin as part 
of the standard of care. This drug is given during every cesarean section immediately after your 
baby is delivered, in order to help the uterus contract well, to prevent bleeding from poor uterus 
contraction. Oxytocin is also the first line treatment for poor uterine contraction. It is possible 
that even with oxytocin being given, the surgeon may think your bleeding is higher than normal. 
If so, they will take several steps to control the bleeding. One of these steps may be giving you a 
drug to stop the bleeding. If the doctors want one of these drugs, we will assign you by chance 
(like flipping a coin) to receive either methylergonovine or carboprost.
If any more drugs are needed to stop the bleeding after that first drug, you will receive the other 
study drug, as would typically be done. Your obstetrician and the nurses in the operating room 
will not know which drug you receive until after the surgery is completed. The anesthesiologist 
will know which drug they are giving to you and will document it in your surgical record. 
Patients in both groups will receive every usual measure of care during their cesarean section and 
after surgery. Being in the study will not change the medications you receive or anything about 
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Research Consent Form
General Template
Version Date:  August 2016
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Subject Identification
your surgical treatment. The only difference for study patients is that the order in which they get 
the drugs to stop bleeding will be ‘by chance’.
At the time of giving the first drug for bleeding, the anesthesiologist will ask the obstetrician to 
rate the ‘uterine tone’, which is a measure of how much your uterus has contracted. The more the 
contraction, the less bleeding you should have. At 10 minutes later, the anesthesiologist will 
again ask the obstetrician to rate the uterine tone, to see if it has improved because of the drug 
they gave.
If you receive the study drug(s), we will collect your basic medical history and the results of your 
blood testing. We will also document information about how your surgery and recovery go. All 
this information will be recorded in a secure electronic document on a password-protected 
computer. The only people with access to this information will be two study investigators. 
At any time, if you wish you may stop being in the study. Your decision will not affect your 
future care in any way. You will continue to receive medications and other treatments to prevent 
and stop bleeding, whether or not you choose to take part in the study.
Also, your participation in this study may be stopped by the study doctor or the institutional 
review board for any of the following reasons: 
• If the study procedures appear to be medically harmful to you 
• If it is discovered that you do not meet the study requirements 
• If it is determined to be in your best interest 
• We stop doing the study for other reasons
A notation that you are taking part in this research study may be made in your electronic medical 
record. Information from the research that relates to your general medical care may be included 
in the record (for example: list of allergies, results of standard blood tests done at the hospital 
labs).
Please ask your study doctor if you have any questions about what information will be included 
in your electronic medical record.
What are the risks and possible discomforts from being in this research 
study?
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Subject Identification
The two drugs used in this study are methylergonovine and carboprost. Serious side effects are 
rare, but may occur in some instances.
Methylergonovine
The most common side effect of methylergonovine is high blood pressure, which in severe cases, 
may be associated with seizures. Other side effects may include:
- headache
- abdominal pain 
- nausea, vomiting or diarrhea
Rare side effects include:
- heart attack or chest pain
- rapid or slow heart rate
- shortness of breath
- blood in the urine
- hallucination
- allergic reaction
- leg cramps
- ringing in the ears
Stroke, numbness and tingling, and dangerous heart rhythms have been reported in patients who 
received methylergonovine.
The onset of methylergonovine is approximately 2-5 minutes and the effects of 
methylergonovine should last no more than 3-6 hours.
Carboprost
The most common side effects of carboprost are flushing, nausea, vomiting and diarrhea and 
fever. Additional side effects may include:
- asthma, difficulty breathing or cough
- high blood pressure, palpitations, chest pain or fast heart rate
- anxiety, dizziness, drowsiness, shivering
- rash
- hot flash, increased thirst 
- stomach pain, urinary or uterine infection
- back pain, leg cramps, muscle pain
- blurry vision or eye pain
Rare reports have occurred of severe allergic reaction to carboprost.
If you have any of these symptoms or any other side effects after receiving one or both of the 
study drugs, you should tell your study doctor right away. You should tell your doctors about all 
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Subject Identification
medications that you are taking (both prescribed and over the counter) to ensure that these drugs 
are safe for you to receive.
There is a small risk of loss of confidentiality. We will minimize this risk by keeping all records 
with your identifying information in a secure and locked area.
What are the possible benefits from being in this research study?
The information gained from this study may benefit future patients by improving our current 
treatment of bleeding after delivery, allowing us to be more effective in stopping this bleeding. 
However, you may not directly benefit from participating in this study.
What other treatments or procedures are available for my condition?
You do not have to participate in this study to be treated for bleeding after delivery. You will 
receive all standard treatments that are needed to control any bleeding that occurs. 
When there is abnormal bleeding after delivery, several measures are taken to control bleeding, 
such as medications to stop the bleeding and sometimes additional surgery. In addition to the 2 
study drugs, methylergonovine and carboprost, other medications used to treat bleeding are:
Oxytocin
Misoprostol
Additional surgical options may include:

Placement of a balloon in the uterus

Exploratory laparotomy, an operation done on the abdomen in order for the surgeon to 
determine the cause of bleeding and fix it

Uterine artery embolization, a minimally invasive procedure done under X-ray, with a 
needle placed in the groin and small particles sent through it to the blood supply of the 
uterus to stop the bleeding in the place it occurs

B-Lynch sutures, a technique for sewing temporary stitches into the uterus to compress it 
and stop severe bleeding

Dilation and evacuation, a surgery in which the obstetrician dilates the cervix and then 
uses instruments to enter the uterus and remove any products of conception that remain 
inside which are causing bleeding

Hysterectomy, a surgery to remove the uterus in cases of uncontrollable bleeding
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Partners HealthCare System
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Version Date:  August 2016
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Subject Identification
Oxytocin is the first and best treatment to prevent and control bleeding after delivery; you will 
receive this drug first, as is standard after all deliveries. If you need additional medication to 
control bleeding, you will receive one of the study drugs, methylergonovine and/or carboprost, as 
part of your participation in this research.  If you need additional treatment afterward, 
misoprostol and repeat doses of the prior drugs will be available to you. Additional surgery may 
be performed if needed. 
Talk with the study doctor if you have questions about any of these treatments or procedures.
Can I still get medical care within Partners if I don’t take part in this 
research study, or if I stop taking part? 
Yes.  Your decision won’t change the medical care you get within Partners now or in the future.  
There will be no penalty, and you won’t lose any benefits you receive now or have a right to 
receive.
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  We will tell you if we learn new 
information that could make you change your mind about taking part in this research study.
What should I do if I want to stop taking part in the study?
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed.
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed.
Will I be paid to take part in this research study?
No payment will be given for participating in this study.
What will I have to pay for if I take part in this research study?
There are no costs to you for participating in this research study. You will not pay for any study-
related items and services. We may bill your health insurer for, among other things, routine items 
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Partners HealthCare System
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Subject Identification
and services you would have received even if you did not take part in the research. You will be 
responsible for payment of any deductibles and co-payments required by your insurer for routine 
care or other billed care, in the same way that you would be responsible for these payments if 
you did not take part in the research. If you have any questions about costs to you that may result 
from taking part in the research, please speak with the study doctors and study staff.
What happens if I am injured as a result of taking part in this research 
study?
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study.  We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury. For example, if the care is billed to your insurer, 
you will be responsible for payment of any deductibles and co-payments required by your 
insurer.
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for an injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form.
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher's name and phone number are listed in the next section of this consent form.
If I have questions or concerns about this research study, whom can I 
call?
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want.  
Dr. Jimin Kim, MD is the person in charge of this research study.  You can call her at 773-960-
4237 M-F 8-5 or after hours have her paged by calling 617-732-6660.  You can also call Dr 
Brian Bateman or Dr Julian Robinson M-F between 8am-5pm at 617-732-5500 with questions 
about this research study. 
If you have questions about the scheduling of appointments or study visits, call Dr Jimin Kim, 
MD at 773-960-4237 .
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Partners HealthCare System
Research Consent Form
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Subject Identification
If you want to speak with someone not directly involved in this research study, please contact 
the Partners Human Research Committee office.  You can call them at 857-282-1900.
You can talk to them about:

Your rights as a research subject

Your concerns about the research

A complaint about the research
Also, if you feel pressured to take part in this research study, or to continue with it, they want to 
know and can help.
If I take part in this research study, how will you protect my privacy?
During this research, identifiable information about your health will be collected.  In the rest of 
this section, we refer to this information simply as “health information.”  In general, under 
federal law, health information is private.  However, there are exceptions to this rule, and you 
should know who may be able to see, use, and share your health information for research and 
why they may need to do so.   
In this study, we may collect health information about you from:

Past, present, and future medical records

Research procedures, including research office visits, tests, interviews, and 
questionnaires
Who may see, use, and share your identifiable health information and why they may 
need to do so:

Partners research staff involved in this study

The sponsor(s) of this study, and the people or groups it hires to help perform this 
research

Other researchers and medical centers that are part of this study and their ethics boards

A group that oversees the data (study information) and safety of this research

Non-research staff within Partners who need this information to do their jobs (such as for 
treatment, payment (billing), or health care operations)

The Partners ethics board that oversees the research and the Partners research quality 
improvement programs.
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Partners HealthCare System
Research Consent Form
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Subject Identification

People from organizations that provide independent accreditation and oversight of 
hospitals and research

People or groups that we hire to do work for us, such as data storage companies, insurers, 
and lawyers

Federal and state agencies (such as the Food and Drug Administration, the Department of 
Health and Human Services, the National Institutes of Health, and other US or foreign 
government bodies that oversee or review research) 

Public health and safety authorities (for example, if we learn information that could mean 
harm to you or others, we may need to report this, as required by law)

Other:  none
Some people or groups who get your health information might not have to follow the same 
privacy rules that we follow and might use or share your health information without your 
permission in ways that are not described in this form.  For example, we understand that the 
sponsor of this study may use your health information to perform additional research on various 
products or conditions, to obtain regulatory approval of its products, to propose new products, 
and to oversee and improve its products’ performance.  We share your health information only 
when we must, and we ask anyone who receives it from us to take measures to protect your 
privacy.  The sponsor has agreed that it will not contact you without your permission and will not 
use or share your information for any mailing or marketing list.  However, once your information 
is shared outside Partners, we cannot control all the ways that others use or share it and cannot 
promise that it will remain private.
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your health information.
The results of this research study may be published in a medical book or journal, or used to teach 
others.  However, your name or other identifying information will not be used for these purposes 
without your specific permission.
Your Privacy Rights
You have the right not to sign this form that allows us to use and share your health information 
for research; however, if you don’t sign it, you can’t take part in this research study.   
You have the right to withdraw your permission for us to use or share your health information 
for this research study.  If you want to withdraw your permission, you must notify the person in 
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Partners HealthCare System
Research Consent Form
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Subject Identification
charge of this research study in writing.  Once permission is withdrawn, you cannot continue to 
take part in the study.
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others.
You have the right to see and get a copy of your health information that is used or shared for 
treatment or for payment.  To ask for this information, please contact the person in charge of this 
research study.  You may only get such information after the research is finished. 
Informed Consent and Authorization
Statement of Person Giving Informed Consent and Authorization

I have read this consent form.

This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study.

I have had the opportunity to ask questions.

I understand the information given to me.
Signature of Subject:
I give my consent to take part in this research study and agree to allow my health information to 
be used and shared as described above.
Subject
Date
Time (optional)
Signature of Study Doctor or Person Obtaining Consent:
Statement of Study Doctor or Person Obtaining Consent
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Partners HealthCare System
Research Consent Form
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Version Date:  August 2016
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Subject Identification

I have explained the research to the study subject.

I have answered all questions about this research study to the best of my ability.
Study Doctor or Person Obtaining Consent
Date
Time (optional)
Consent of Non-English Speaking Subjects Using the “Short Form” in the 
Subject’s Spoken Language
Statement of Hospital Medical Interpreter
As someone who understands both English and the language spoken by the subject, I interpreted, 
in the subject's language, the researcher's presentation of the English consent form.  The subject 
was given the opportunity to ask questions.
Hospital Medical Interpreter
Date
Time (optional)
Consent Form Version:  8/17/2021
Page 39 of 99

DETAILED PROTOCOL
Second-line Uterotonics in Postpartum Hemorrhage: A Randomized 
Clinical Trial 
Version date: 04/19/2022
I.
BACKGROUND AND SIGNIFICANCE
Primary postpartum hemorrhage (PPH) is defined by the American College of Obstetricians and 
Gynecologists as a cumulative blood loss of >1000mL within 24 hours of the birth process. PPH remains 
the leading source of maternal morbidity and mortality worldwide with uterine atony identified as the 
underlying cause in up to 80% of cases.1 2Between 1994 and 2006, the rate of PPH increased by 42% in the 
United States, raising further concern for this problem.3 
Treatment of PPH typically begins with administration of exogenous oxytocin, a hormone responsible for 
uterine contraction. Oxytocin is given prophylactically during the third stage of labor to decrease the risk 
of PPH and is considered the first-line medical treatment for PPH.4 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). 5 The 
comparative efficacy of these two drugs is unknown and as a result, there is wide variability in the usage 
of these second-line uterotonics.6 
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.7 Given the equivalent role for these two agents, the decision to use either 
methylergonovine or carboprost is usually based on provider preference in the absence of any 
contraindications. Internationally, there is a similar lack of consensus, with guidelines recommending 
oxytocin, methylergonovine, carboprost, or misoprostol in varying order. 
Recent evidence suggests that methylergonovine is the most commonly used second-line uterotonic 
agent across the United States with carboprost being the next most frequent.5,8 One recent observational 
study suggests that methylergonovine may be superior to carboprost in reducing PPH-related morbidity, 
although residual confounding may be responsible for this finding.9 There are no randomized trials 
comparing clinical outcomes of methylergonovine vs carboprost in PPH to date. Since PPH remains an 
unpredictable and emergent event, high quality prospective trials are challenging to perform and scarce. 
This research is nonetheless critical to provide high quality evidence for the optimal management of 
atonic PPH.
The aim of this study is to evaluate in a randomized fashion the comparative efficacy of methylergonovine 
and carboprost for treating atonic PPH. In the event of PPH, patients undergoing non-emergent cesarean 
section (C/S) with no contraindications to either drug will be randomized to receive one of the two 
equivalent agents in a blinded fashion after oxytocin. All patients will be managed as per standard of care 
at the Brigham and Women’s Hospital. The uterine tone will be estimated by a blinded obstetrician before 
and after study drug administration. Several secondary outcomes relevant to efficacy and safety of the 
drugs will also be evaluated. 
Page 40 of 99

II.
SPECIFIC AIMS (Research Objectives) 
We hypothesize that the administration of methergonovine will be associated with a 1 point greater 
reduction in uterine tone (on a 0-10 scale) at 10 minutes after administration compared to carboprost. 
1.
The primary outcome will be the uterine tone score on a 0 to 10 scale 10 minutes after 
administering the study drug. A score of 0 will mean the uterus has ‘no tone’. A score of 
10 will mean there is  ‘excellent tone’.
2.
Secondary outcomes will include:
a)
change in uterine tone from the time of study drug administration to 5 
minutes later,
b)
administration of an additional uterotonic agent after the first study drug 
c)
number of transfused blood products within 24 hours from the time of 
delivery,
d)
any surgical intervention intended to control bleeding: i.e. Bakri balloon, 
O’Leary stitch, d&e, exploratory laparotomy, B-Lynch sutures, hysterectomy 
or interventional radiology artery embolization,
e)
intraoperative quantitatively measured blood loss (QBL), 
f)
pre-delivery to postpartum change in serum hemoglobin, 
g)
vasopressor requirement or hypovolemic shock
h)
postpartum admission to the intensive care unit (ICU), 
i)
need for postoperative mechanical ventilation, 
j)
nausea, vomiting, or diarrhea, abdominal pain, shortness of breath, 
headache, blurred vision, anxiety, chest pain, sweating, or palpitations within 
2 hours postpartum
k)
hypertensive emergency (SBP>/=160 or DBP>/=110)
l)
EKG changes indicative of myocardial ischemia, 
m) acute renal dysfunction, 
n)
length of postoperative hospital stay, 
o)
postpartum acute lung injury or circulatory fluid overload in the context of 
blood product transfusion, 
p)
allergic reaction deemed the result of blood product transfusion
III. 
SUBJECT SELECTION
Inclusion Criteria/Exclusion Criteria: 
Inclusion criteria will be all of the following: American Society of Anesthesiologists (ASA) I, II or III health 
status (minimal to no systemic disease), age between 18 and 50 yrs, and planned elective C/S or non-
emergent C/S after labor, with suspected uterine atony at the time of delivery despite the administration 
of oxytocin.
Exclusion criteria for enrollment in the study will include any of the following: patients with essential 
hypertension or any hypertensive disorder of pregnancy, patients with cardiovascular disease, patients 
with active asthma (i.e. bronchodilator usage in the past 24 months), non-English speaking patients who 
are undergoing urgent, non-scheduled C/S, patients who refuse to accept blood transfusion (e.g. 
Jehovah’s Witnesses), patients with a known coagulopathy or abnormal baseline coagulation profile, 
patients with known or suspected hypersensitivity to either of the two study drugs, and patients with 
known or suspected delayed PPH after leaving the operating room from the cesarean delivery.
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Source of Subjects and Recruitment Methods:
Subjects will be recruited from women admitted to the labor & delivery (L&D) floor at the Brigham and 
Women’s Hospital undergoing cesarean delivery who meet selection criteria as above. 
IV. 
SUBJECT ENROLLMENT
Prior to admission, all participating obstetricians will provide their patients with the study Flier and 
consent form, which will be given to patients at their 28-week obstetric visit. This will allow potential 
subjects ample time to consider participation in the study. In addition, participating obstetricians will 
request consent from their patients to be contacted for research purposes, to provide a reminder of the 
study protocol closer to patients’ delivery date. Those patients who agree to be contacted and are at 37 
weeks gestational age or greater and eligible for the study (planning either vaginal or cesarean delivery) 
will be sent an email with the study’s Flier and consent form attached from the research assistant. The 
email will be sent securely to protect patient confidentiality, in accordance with MGB Privacy and Security 
guidelines.
At the time of admission to the pre-operative area or labor and delivery unit, patients will be pre-
screened for eligibility using the OB Pre-Screen questionnaire. The screening process will be documented 
in a Pre Screening Log without patient identifiers (patients will be logged using the first initial of their last 
name). All eligible patients undergoing planned elective C/S will be provided the Flier and consent form. A 
physician investigator (either the principal investigator or one of the co-investigators) who is not involved 
in the patient’s care will review and discuss the study plan at this time, allowing subjects the opportunity 
to ask questions and address any of their concerns or any issues surrounding the study. Non-English 
speaking patients undergoing planned elective C/S will be interviewed with the assistance of an official in-
person BWH medical interpreter. The consent will be verbally translated in full to their native language by 
the interpreter. Subjects interested in participating will then be consented by the principal investigator or 
physician co-investigator and enrolled in the study. 
In the setting of the current COVID-19 pandemic, all study staff will wear appropriate PPE (as dictated by 
Partners-wide official policy) while working and during any conversation with study subjects. In addition, 
patients will only be approached in their room by a study physician to minimize personal contact, at which 
time they will discuss the study and obtain informed consent from those patients interested in 
participation. There will be attention to appropriate social distancing, hand hygiene and minimization of 
sharing any physical objects (e.g. pen, clipboard etc.) throughout the conversation with prospective study 
subjects. Should patients be interested in participation, written consent will be accepted.
Patients who are designated to have a C/S delivery after labor due to ‘failure to progress’ will be 
approached in a similar manner for consent at the time of decision for C/S. Non-English speaking patients 
undergoing unscheduled, urgent C/S will not be approached since translators may not be available in a 
timely fashion to assist with consent.
This study will only be conducted in women. Non-English speaking patients undergoing urgent C/S will not 
be approached since translators may not be available in a timely fashion to assist with consent. No other 
vulnerable populations will be specifically targeted, nor will any one group bear a disproportionate share 
of the burdens or benefits of the research.
A total of 1250 women will be enrolled, and 100 randomized in this study based on the power calculation 
included below and allowing for patient withdrawal or loss to followup; women will be assessed for 
eligibility and then randomized to either methylergovonive or carboprost groups with the aim of 
approximately 50 patients per group.
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V. 
STUDY PROCEDURES
All subjects will have an IV placed and baseline labs sent, as is standard for all patients admitted to the 
Center for Women and Newborns Labor and Delivery unit. Baseline labs will include: type and screen and 
complete blood count (CBC).
At the time of delivery, enrolled subjects will be assessed for poor uterine tone despite the administration 
of oxytocin following delivery. If either methylergonovine or carboprost is requested by the obstetrician 
or anesthesiologist, subjects will then be randomized by the anesthesiologist to either 
“methylergovonine” or “carboprost” groups by a computer generated randomization scheme printed on a 
piece of paper in a sealed envelope. The anesthesiologist will then withdraw the appointed medication 
(based on subject randomization) from the O.R. omnicell and administer it without revealing to anyone in 
the O.R. which drug was given. They will document the medication in the subject’s Epic record in the usual 
fashion. 
The obstetrician and nurse, involved in the cases as well as the study investigator will be blinded to the 
study group assignments. All physician co-investigators (with the exception of the principal investigator) 
and the statistician will be blinded to study group assignments throughout the study. As such, these co-
investigators will not be involved in the obstetric care of the study subjects, with the following one 
exception: Every effort will be made to keep the study investigator who consented the subject out of the 
operating room and uninvolved in the subject’s clinical care in all cases. However occasionally, due to 
staffing challenges and clinical acuity of a patient’s case (e.g. massive hemorrhage), the anesthesiology 
attending or fellow who consented the patient may need to be involved in the patient’s intraoperative or 
postoperative care. To minimize any chance of patient coercion and bias in clinical decision-making, the 
consent process will occur first with the study investigator anesthesia provider. Only after consent is 
complete and the patient enrolled will the same anesthesiologist who consented the patient end up 
caring for the patient. This scenario will only occur in situations when a staffing shortage occurs or the 
case requires additional help due to a life-threatening situation. Everything possible will be done to avoid 
that situation. Thus the patient will agree to participate in the study in advance of forming any physician-
patient relationship with the study investigator, and the study investigator will only affect clinical care as a 
helper in case of clinical necessity, not as the leader of clinical decision-making  (i.e. the study investigator 
will not be the primary anesthesiologist of record for the case). 
The study drug will consist of either:
1.
0.2mg methylergovonine, or
2.
0.25mg 15-methyl prostaglandin F2α
The anesthesiologist will administer the study medication in a 1mL syringe intramuscularly in the patient’s 
deltoid muscle. Each patient will have both medications available in the fridge where hemorrhage 
medications are stored, so that the second of the 2 drugs can be easily administered in succession if an 
additional agent is needed.
At the time of administration of the first study drug, the anesthesiologist will ask the obstetrician to rate 
the uterine tone on a scale of 0 to 10 (0 being with ‘no tone’, 10 being ‘excellent tone’). The 
anesthesiologist will then set a timer. After administration of the study drug, patient care will receive our 
usual standard of care. At 5 and 10 minutes from the onset of timing, the anesthesiologist will once again 
ask the obstetrician for a rating of uterine tone between 0 and 10. These values will be recorded by the 
anesthesiologist on a Uterine Tone Score Intraop Data Collection sheet included in the sealed envelope 
provided by the investigator.
Page 43 of 99

If an additional uterotonic agent is requested by the obstetrician, the unblinded anesthesiologist will 
prepare the other drug, again in a 1mL syringe. Timing of this administration will be noted on the study 
record sheet. All other medications and interventions will proceed as usual and in an unblinded fashion.; If 
uterine tone remains unsatisfactory, identity of the study drugs will remain blinded, if possible. Any 
repeat administrations of carboprost or methylergonovine will be given by the anesthesiologist based on 
the timing of administration of the 2nd study drug.
The obstetric physicians and nurses caring for the patient will document quantitatively measured blood 
loss during the delivery. The volume of blood mixed with amniotic fluid in the graduated suction jars and 
the number of sponges soaked with blood will be noted. In addition to baseline serum hematocrit, 
postpartum serum hematocrit and platelet count, will be evaluated on the first postoperative day after 
C/S. The change in serum hematocrit will be compared among study groups. 
At the end of the C/S, the anesthesiologist will complete the Randomization Sheet, documenting the 
patient MRN and study ID number. They will return the Randomization sheet and the Uterine Tone Score 
Intraop Data Collection sheet in the [previously sealed] envelope to a locked room on L&D where all paper 
documents for the study will be temporarily stored until the unblinded principal investigator collects the 
sheets (on the same day as subject enrollment) and brings them to a locked filing cabinet in a locked 
office to which only the principal investigator has access. 
Within the first 24 hours after delivery, but no sooner than the time of patient transfer from the labor and 
delivery floor to the postpartum unit, Between 2-4 hours postpartum and again between 18-24 hours 
postpartum, a blinded study investigator who is not involved in the subject’s clinical care will interview 
the patient by phone (to avoid physical contact and minimize the risk for COVID-10 transmission) and 
record the information from the interview on the corresponding ‘2-4 Hr Interview Guide’ or ’18-24 Hr 
Interview Guide’. This will allow them to assess subjective side effects of the study medication such as G.I. 
upset, dizziness, shortness of breath, palpitations or chest pain.  Non-English speaking patients will be 
interviewed in person with the assistance of an in-person interpreter from BWH Interpreter Services.
Subject randomization, patient MRN and the linked study ID number will be documented on a separate 
form in the secure electronic database, REDCap database by the unblinded principal investigator. This 
form will be visible only to the principal investigator. An unblinded study investigator (i.e. the principal 
investigator, or a research assistant, when one is hired in the future) with access to REDCap will be 
responsible for collecting and entering all primary and secondary outcomes from the Uterine Tone Score 
Intraop Data Collection sheet, the 2-4 Hour Interview Guide and the 18-24 Hour Interview Guide and Epic 
medical records (including side-effects of study medications) into REDCap. Subject randomization will be 
documented, on a separate form in the database to which only the principal investigator has access, in 
order to preserve the integrity of the data collection and entry.
The need for blood product administration and quantity of each component given within 24hrs after 
cesarean section will be recorded. In addition, the investigator will record any additional interventions 
performed to halt bleeding, such as Bakri balloon placement, B-Lynch sutures, uterine artery embolization 
or hysterectomy.
Total intravenous fluids given from start to conclusion of the delivery will be recorded. The use of 
vasopressors, uterotonic agents, anti-emetic agents will be recorded.  Length of stay and any 
postoperative complications occurring during the hospital stay will be documented at the time of hospital 
discharge. 
All clinical and other data obtained during this study will be considered confidential.  Procedures to limit 
access to subject charts and information from the study will be in place. Study participant data will be de-
Page 44 of 99

identified upon entry into the data collection tool and will be known only to the investigators. No 
information regarding the identity of individual subjects will be utilized for publications.  
Primary Endpoint
1.
Uterine tone score as recorded at 10 minutes following the administration of the second-line 
uterotonic.
Secondary Endpoints
1.
Need for an additional uterotonic agent after the study drug,
2.
Uterine tone score as recorded at 5 minutes following the administration of the second-line 
uterotonic,
3.
Number of units of blood products transfused from t0 to tfinal (t0 = time of delivery; tfinal = 24 hours 
after delivery)
4.
Need for a surgical or radiologic intervention to control bleeding.
5.
Quantitative intrapartum blood loss
6.
Pre- vs post-delivery hemoglobin values.
7.
Maternal morbidity: admission to the intensive care unit postpartum, postoperative infection, 
transfusion reaction, acute kidney injury, hypovolemic shock, or vasopressor requirement, study 
medication side effects.
Subject Costs
There will be no extra costs to the subjects related to the conduct of this study, as there are no additional 
medications or tests to be used that are not already the routine standard of care. Methylergonovine and 
carboprost used in the study will be stocked as needed by the inpatient hospital pharmacy in the usual 
manner. Subjects and/or their insurance companies will be responsible for all their medical and surgical 
procedures and care as associated with their delivery.  
VI. 
BIOSTATISTICAL ANALYSIS
a. Specific data variables being collected for the study (e.g., data collection sheets).
Baseline patient characteristics will be collected and documented on data collection sheets. These 
characteristics will include: 
1.
patient MRN
2.
randomization group
3.
age
4.
height, weight, BMI
5.
gravidity and parity
6.
baseline hematocrit and platelet count measured at the time of admission or on the day 
of delivery
b. Statistical methods
The balance of patient characteristics between the two groups before intervention will be evaluated using 
standardized differences. Shapiro-Wilk test will be used to confirm whether the primary endpoint, uterine 
tone score 10 minutes after drug administration, satisfies the normality assumption. Multiple linear 
regression will be conducted when normality assumption satisfied. In the case when the normality 
assumption is not established, log transformation/box-cox transformation of the outcome will be carried 
out before modeling. For secondary endpoints that are dichotomous, logistic regression will be used to 
Page 45 of 99

examine the intervention effect after adjusting for potential confounders. For continuous secondary 
endpoints, such as intrapartum blood loss, we will evaluate its distribution before performing appropriate 
modeling. Trial site will be included as a covariate in all models to adjust for the stratification of 
randomization by hospital. 
c. Power analysis (e.g., sample size, evaluable subjects, etc.) 
Assuming a common within-group standard deviation in uterine tone score of 1.9 points, a minimum 
sample size of 41 randomized patients per group would provide 80% power at a two-sided alpha level of 
0.05 to detect a 1.2 point difference in mean uterine tone score at 10 minutes post secondary uterotonic 
administration between groups using a two-sample t-test. A total of 50 patients per group (100 patients 
total) will need to be randomized be enrolled to account for protocol violations. Since we currently 
perform 175 C/S monthly at BWH, and approximately 20 patients undergoing non-emergent C/S receive 
methergine or hemabate for uterine atony each month, we anticipate needing to enroll 1250 patients in 
total to be able to randomize 100 patients to receive the study intervention. 
The within-group standard deviation estimate of 1.9 is based on the observed standard deviation in 
uterine tone score (averaged between raters) at 10 minutes post-delivery amongst patients in our 
previous study (The Inter-rater Reliability of a 0 to 10 Uterine Tone Score) who received a secondary 
uterotonic. The minimal clinically important difference of 1.2 points is based on the upper limit of the 90% 
confidence interval for the difference in uterine tone score (averaged between raters) at 3 minutes post-
delivery between patients who did and did not receive a secondary uterotonic (difference in means [90% 
CI]: -2.3 [-3.5, -1.2]).
VII. 
RISKS AND DISCOMFORTS 
Adverse reactions to methylergonovine include increased blood pressure, seizure, dizziness and 
headache, and nausea, vomiting, diarrhea and abdominal pain from uterine contractions. Rare effects 
include chest pain, myocardial infarction, coronary vasospasm, tachycardia, dyspnea, and hematuria. A 
large retrospective study of over 2 million parturients found no significantly increased risk of acute 
coronary syndrome or acute myocardial infarction after receiving methylergonovine.10 ACOG 
recommendations nonetheless state that methylergonovine should be avoided in patients with 
hypertension and cardiovascular disease.7
The most common adverse reactions to carboprost include nausea, vomiting, diarrhea, as well as 
headache, myalgias, increased temperature and flushing. Due to its stimulation of smooth muscle 
contraction, modest increases in blood pressure may be seen, but these are generally clinically 
insignificant. Additionally, bronchospasm, abnormal ventilation-perfusion and hypoxia may occur, and 
may be particularly severe in patients susceptible to these complications. Carboprost is therefore 
contraindicated in patients with active asthma.
Patients with any contraindication to either of the study drugs will be excluded from participation in the 
study. Patients with a diagnosis of asthma will be interviewed to confirm if their asthma is active. Any 
patient who has used a bronchodilator within the past 24 months will be considered to have active 
asthma and will be excluded. If a patient carries a diagnosis of ‘childhood asthma’ and/or has not needed 
a bronchodilator for >24 months, they will be considered eligible to participate in the study. After 
enrollment, patients will be evaluated for all of the above side effects by a clinical investigator between at 
time of transfer to the postpartum floor and again between 18 to 24 hours after delivery. The obstetric 6-
Page 46 of 99

week postpartum follow-up record will be reviewed by a clinical investigator to screen for thrombotic 
events or other side effects.
Administration of methylergonovine and carboprost will occur after delivery of the fetus. Single 
intramuscular doses of methylergonovine have been shown to decrease serum prolactin levels compared 
to women receiving placebo. However, milk production, rates of exclusive breastfeeding and infant weigh 
gain have not been found to differ.11-15 Case reports indicate a possible association of methylergonovine 
with tachycardia, vomiting, diarrhea and agitation in the infant. A recent prospective observational study 
comparing postpartum use of methylergonovine with control found no difference in lactation or neonatal 
complications in the infants of mothers who received methylergonovine. 16 
It is unknown whether carboprost is excreted in human milk and there are currently no studies 
determining the infant risk from carboprost in breastfeeding mothers.
No additional inpatient hospital time is anticipated by participating in this study.
VIII. 
POTENTIAL BENEFITS
The potential benefits of receiving methylergonovine or carboprost during cesarean delivery include a 
reduction in PPH, a lower risk of transfusion requirement and other interventions used to control PPH.  
On a population-based level, the potential benefit of this study lies in an improvement in our 
understanding and management of PPH by determining the superior second-line uterotonic between 
methylergonovine and carboprost. This in turn could lead to a significant decrease in maternal morbidity 
due to adverse events associated with PPH. 
IX. 
MONITORING AND QUALITY ASSURANCE
A physician investigator will be present during the entire consent, enrollment and conduct of the study.  
Criteria for early termination from the study will be observed. Two definitions of early endpoints will be 
utilized:  
1.
Subject decision for withdrawal from participation at any time.  
2.
Any operative or medical condition changes prior to or during the entire study period 
deemed unacceptable by the obstetrician, anesthesiologist, or physician investigator.  
The principal investigator will review all forms and data with every 5 th subject to ensure completeness, 
accuracy and adherence to the protocol. There will be no data safety monitoring board (DSMB) in this 
study. In place of a DSMB, the Principal Investigator will take full responsibility for standardized review of 
recruitment at the above frequency, to ensure adherence to protocol, detection of minor or major 
adverse events (AE’s), and timely reporting of such events to the IRB with halting of the study if necessary 
(for any AE’s). 
All AE’s, whether or not they are considered related to the study, shall be recorded on the Adverse 
Experience Form within the Case Report Forms (CRFs).  The study investigators will comply with the Food 
and Drug Administration (FDA) regulations requiring the expedited reporting of any AE that is Serious, 
Unexpected, and Associated with the use of the study drug.  AEs will be reported to the PHRC in 
accordance with the PHRC Policy on Unanticipated Problems Involving Risks to Subjects or Others, 
including Adverse Events.
Page 47 of 99

Serious AE’s include hemodynamic instability requiring epinephrine or norepinephrine or resulting in loss 
of consciousness or cardiovascular collapse, allergic or anaphylactic reactions to study solution infused, 
major respiratory complication during hospital admission, or seizure activity.  Should any of these events 
occur, the Principal Investigator will be contacted immediately, the study code broken, and the case 
reviewed.  Serious AE’s that occur higher than the expected native incidence will warrant temporarily 
halting the study and consultation with the Directors of Obstetric Anesthesia (Brian Bateman, MD) and 
Labor and Delivery (Julian Robinson, MD).
The standard causality criteria will be used to determine these AE’s.  Investigators will notify the principal 
investigator immediately of all SAEs.  If necessary, any additional relevant information will be collected 
and reported.  All AE’s will be reported to the IRB per the HRC guidelines.
X. 
REFERENCES
1.
Combs CA, Murphy EL, Laros RK, Jr. Factors associated with postpartum hemorrhage with vaginal 
birth. Obstet Gynecol. 1991;77(1):69-76.
2.
Dildy GA, 3rd. Postpartum hemorrhage: new management options. Clin Obstet Gynecol. 
2002;45(2):330-344.
3.
Callaghan WM, Kuklina EV, Berg CJ. Trends in postpartum hemorrhage: United States, 1994-
2006. Am J Obstet Gynecol. 2010;202(4):353 e351-356.
4.
Westhoff G, Cotter AM, Tolosa JE. Prophylactic oxytocin for the third stage of labour to prevent 
postpartum haemorrhage. Cochrane Database Syst Rev. 2013(10):CD001808.
5.
Bateman BT, Tsen LC, Liu J, Butwick AJ, Huybrechts KF. Patterns of second-line uterotonic use in a 
large sample of hospitalizations for childbirth in the United States: 2007-2011. Anesth Analg. 
2014;119(6):1344-1349.
6.
Likis FE, Sathe NA, Morgans AK, et al. Management of Postpartum Hemorrhage. Rockville 
(MD)2015.
7.
Committee on Practice B-O. Practice Bulletin No. 183: Postpartum Hemorrhage. Obstet Gynecol. 
2017;130(4):e168-e186.
8.
Seligman K, Ramachandran B, Hegde P, et al. Obstetric interventions and maternal morbidity 
among women who experience severe postpartum hemorrhage during cesarean delivery. Int J 
Obstet Anesth. 2017;31:27-36.
9.
Butwick AJ, Carvalho B, Blumenfeld YJ, El-Sayed YY, Nelson LM, Bateman BT. Second-line 
uterotonics and the risk of hemorrhage-related morbidity. Am J Obstet Gynecol. 2015;212(5):642 
e641-647.
10.
Bateman BT, Huybrechts KF, Hernandez-Diaz S, Liu J, Ecker JL, Avorn J. Methylergonovine 
maleate and the risk of myocardial ischemia and infarction. Am J Obstet Gynecol. 
2013;209(5):459 e451-459 e413.
11.
Perez-Lopez FR, Delvoye P, Denayer P, L'Hermite M, Roncero MC, Robyn C. Effect of 
methylergobasine maleate on serum gonadotrophin and prolactin in humans. Acta Endocrinol 
(Copenh). 1975;79(4):644-657.
12.
Weiss G, Klein S, Shenkman L, Kataoka K, Hollander CS. Effect of methylergonovine on puerperal 
prolactin secretion. Obstet Gynecol. 1975;46(2):209-210.
13.
Jolivet A, Robyn C, Huraux-Rendu C, Gautray JP. [Effect of ergot alkaloid derivatives on milk 
secretion in the immediate postpartum period]. J Gynecol Obstet Biol Reprod (Paris). 
1978;7(1):129-134.
14.
Javier del Castillo F, Ramirez BM, Diaz-Infante Ibarra A. [Effect of methylergovine on the 
secretion of prolactin in childbirth and the puerperium]. Ginecol Obstet Mex. 1980;48(289):311-
316.
Page 48 of 99

15.
Gonzalez P, Gayan P, Pineda G, Herrera R, Leyton M. [Plasma prolactin in the puerperium and its 
relation to the use of methylergonovine maleate]. Rev Chil Obstet Ginecol. 1984;49(3):149-155.
16.
Gilad O, Merlob P, Stahl B, Averbuch N, Klinger G. Outcome of breastfed infants following post-
partum methylergonovine treatment. J Matern Fetal Neonatal Med. 2017;30(13):1569-1573.
Page 49 of 99

MRN
Study
Number
DOB
DOS
Surgeons
Anesthesiolo
gist
Page 50 of 99

INTRAOP
Study
Number
Preop Hct
5 Min Tone
10 Min Tone
2nd Study
Drug Given?
Misoprostol
QBL
Page 51 of 99

Crystalloid Colloid RBCs FFP
Platelets TXA
Riastap UOP
Pressors
(total mg)
Ischemic EKG
Changes
Page 52 of 99

INTRA/POST 6hrs POSTOP 24hrs POSTOP 
Surgical or IR
Interventions Hct
QBL
RBCs
FFP
Platelets
TXA
Page 53 of 99

Riastap
Pressors
Misoprostol
Page 54 of 99

Study
Number
Nausea
Vomiting
Diarrhea
Dyspnea
Headache
Blurred
Vision
Page 55 of 99

Severe Anxiety
Chest Pain
Diaphoresis SBP>/=160
If>160, Max
SBP
DBP>/=110,
Page 56 of 99

If>110, Max
DBP
Avg UOP/hr
Page 57 of 99

Study
Number
Hospital LOS
ICU
Admission
Hypovolemic
Shock (blood
loss + signs end-
organ
malperfusion)
Postop
Mechanical
Ventilation
TRALI/TACO
Page 58 of 99

Allergic
Transfusion
Reaction
Other Transfusion-
related or
Bleeding
Complications
Page 59 of 99

Study Number:
2nd Uterotonic? (Y / N)       
Timing of 2nd drug (if given):
Ischemic changes (ECG changes)? (Y / N)
QBL (including amniotic fluid):
Estimated Amniotic Fluid volume:
Time
0 min
5 min
10 min 
Score 
 
 
 
Page 60 of 99

Bleeding after Childbirth
Did you know? 
Bleeding after childbirth can cause significant complications in
moms
Our team of BWH OB Anesthesiologists…
Is comparing 2 of the most commonly used drugs for excess bl
after delivery
Is working to determine which of these 2 drugs may be the mos
effective
If you are having a cesarean section, you might be eligible f
study:
You will receive the standard of care at ALL times
Every medication you receive will be FDA approved and safe fo
and your baby
You will receive all the usual treatments for bleeding, but the or
which you receive the 2 interchangeable medications will be pre
decided
Your medical information will be examined by additional doctor
assured, this information is ALWAYS kept confidential
Please help us keep moms safe after delivery! To learn mor
To find out if this study is right for you, please contact
Jimin Kim, MD, Email: jjkim@bwh.harvard.edu, Location: CWN L1, 75 Francis Street, Boston MA 02115
BRIGHAM AND 
WOMEN'S HOSPITAL
HARVARD MEDICAL 
SCHOOL
Page 61 of 99

18-24 HR POSTPARTUM 
BLINDED INTERVIEW GUIDE
SECOND-LINE UTEROTONICS in PPH STUDY
Please DO NOT access the patient’s record prior to completing this form!
Did the patient have any of the following before transfer to the postpartum floor?
YES
NO
Nausea?
☐
☐
Vomiting?
☐
☐
Diarrhea?
☐
☐
Shortness of Breath? 
☐
☐
Headache?
☐
☐
Blurred Vision?
☐
☐
Severe Anxiety?
☐
☐
Chest Pain?
☐
☐
Abnormal Sweating?
☐
☐
Patient Name: ___________________________________
MRN: __________________________________________
Study Number: __________________________________
Date/Time of Interview: ________________________________
Questions or Concerns:
Jimin Kim, MD 
e: jjkim@bwh.harvard.edu 
pg: 38918
Page 62 of 99

2-4 HR POSTPARTUM 
BLINDED INTERVIEW GUIDE
SECOND-LINE UTEROTONICS in PPH STUDY
Please DO NOT access the patient’s record prior to completing this form!
Did the patient have any of the following before transfer to the postpartum floor?
YES
NO
Nausea?
☐
☐
Vomiting?
☐
☐
Diarrhea?
☐
☐
Shortness of Breath? 
☐
☐
Headache?
☐
☐
Blurred Vision?
☐
☐
Severe Anxiety?
☐
☐
Chest Pain?
☐
☐
Abnormal Sweating?
☐
☐
Patient Name: ___________________________________
MRN: __________________________________________
Study Number: __________________________________
Date/Time of Interview: ________________________________
Questions or Concerns:
Jimin Kim, MD 
e: jjkim@bwh.harvard.edu 
pg: 38918
Page 63 of 99

 
Version 2021.06.13 
Page 1 of 1 
 
 
 
Continuing Review Adverse Event Attestation 
 
 
Principal Investigator: 
Jimin Kim, MD 
 
Project Title: 
Second-line Uterotonics in Postpartum Hemorrhage: A Randomized 
Clinical Trial   
 
Date Completed: 
04/05/2022 
 
 
• 
PI to complete Adverse Event Attestation at the time of Continuing Review. 
• 
PI/Staff to upload completed attestation to Insight in place of Adverse Event Log with Continuing 
Review application. 
 
 
By signing off on this Insight application, PI attests to the following: 
 
 I acknowledge the importance of adverse event tracking as a means of evaluating subject safety. 
 
 I have reviewed the Mass General Brigham policy on Reporting Unanticipated Problems .  
 
 I attest that I/my team are keeping an Adverse Event (AE) Log. 
 
 I have reviewed the AE Log associated with this study and find  
 
 No adverse events have occurred so far during the study period of the trial. 
 
 All expected adverse events are recorded on the log and are commensurate with the 
known risks of the approved study.   
 
 Per above policy, all unanticipated problems indicating new or increased risks to 
subjects (including any unexpected adverse events) have been reported promptly 
(within 5 business days/7 calendar days of becoming aware) to the IRB and are recorded 
on the log.  
 
 
Page 64 of 99
X
X
X
X
X

________________________________________________________________________________________________________
Northwestern University has an approved Federalwide Assurance with the Department of Health and Human Services: 
FWA00001549.
HRP-701 / v03092021
APPROVAL OF NEW STUDY
DATE:
April 12, 2021
TO:
Dr. Paloma Toledo
FROM:  Office of the IRB
DETERMINATION DATE:
4/12/2021
APPROVAL DATE:  
4/2/2021
EXPIRATION DATE:  
4/1/2022
The Northwestern University IRB reviewed and approved the submission described below:
Type of Submission:
Initial Study
Review Level:
Committee
Title of Study:
Second Line Uterotonics in Postpartum Hemorrhage: A Randomized 
Clinical Trial
Principal Investigator:
Paloma Toledo
IRB ID:
STU00214439
Funding Source:
Name: Anesthesiology
Documents Reviewed:
• Local Protocol Amendment 04/07/2021, Category: IRB Protocol;
• Carboprost Med Package Insert, Category: Drug Attachment;
• Uterine Tone Score, Category: Data Collection Tools;
• Brigham Harvard Invitation Letter 03.05.2020, Category: Other;
• Partners IRB Brigham Protocol, Category: IRB Protocol;
• 2-4 hour Data Collection, Category: Data Collection Tools;
• Partners IRB approval  05/27/2020, Category: Approval/Authorization 
Letter;
• 18-24 Hour Data Collection, Category: Data Collection Tools;
• Partners IRB approval 10.10.2018, Category: Approval/Authorization 
Letter;
• Methergine Med Package Insert, Category: Drug Attachment;
• Consent V 1.0 04/09/2021, Category: Consent Form;
Special Determination(s):
Pregnant women;
The panel agreed that the study is no more than minimal risk to pregnant 
patients, as activities are standard of care.
Clinical Trial:
Yes
In conducting this study, you are required to follow the requirements listed in the Northwestern 
University (NU) Investigator Manual (HRP-103), which can be found by navigating to the policy section 
of the IRB website.  Additionally, as Principal Investigator (PI) of this research study, you are expected to 
Page 65 of 99

Paloma Toledo
STU00214439
Page 2 of 2
________________________________________________________________________________________________________
Northwestern University has an approved Federalwide Assurance with the Department of Health and Human Services: 
FWA00001549.
HRP-701 / v03092021
adhere to the investigator responsibilities outlined in the “What are my obligations as Investigator in order 
to conduct Human Research” section of the Investigator Manual (HRP-103).
If your study is a clinical trial, there are additional requirements including trial registration and results 
reporting on ClinicalTrials.gov.  Federally-funded clinical trials are also required to post one IRB 
approved consent form, used during enrollment, on a publicly available federal website such as 
ClinicalTrials.gov.  Please visit the clinical trials page on the IRB website for more information.  If you 
would like an account created or need other assistance with ClinicalTrials.gov, please email 
clinicaltrials.gov@northwestern.edu.
If you are unable to complete the study within the approval period, you will need to submit a continuing 
review to renew the study.  The continuing review should be submitted no more than 60 days and no less 
than 30 days prior to the expiration date.
NU IRB approval does not constitute or guarantee institutional approval and/or support.  Investigators and 
study team members must comply with all applicable federal, state, and local laws, as well as NU Policies 
and Procedures, which may include obtaining approval for your research activities from other individuals 
or entities.
For IRB-related questions, please consult the NU IRB website at http://irb.northwestern.edu.  For general 
research questions, please consult the NU Office for Research website at www.research.northwestern.edu.
Additionally, please note that the analyst who you worked with during the initial review and approval of 
your study is not the analyst that is responsible for the review of any subsequent modifications, 
continuing reviews, or RNIs.  As such, please direct any further questions about modifications, continuing 
reviews, or RNIs to the analyst assigned to the subsequent submission. 
Page 66 of 99

 
 
 
 
  
 
 
Methergine®
 
(methylergonovine maleate) 
 
Tablets, USP 
 
(methylergonovine maleate) 
 
Injection, USP 
Rx only 
DESCRIPTION 
Methergine® (methylergonovine maleate) is a semi­synthetic ergot alkaloid used for the prevention and 
control of postpartum hemorrhage. 
Methergine is available in sterile ampuls of 1 mL, containing 0.2 mg methylergonovine maleate for 
intramuscular or intravenous injection and in tablets for oral ingestion containing 0.2 mg 
methylergonovine maleate. 
Tablets 
Active Ingredient:  methylergonovine maleate, USP, 0.2 mg.  
Inactive Ingredients:  acacia, carnauba wax, D&C Red #7, FD&C Blue #1, gelatin special, lactose,  
maleic acid, mixed parabens, povidone, sodium benzoate, sodium hydroxide, starch, stearic acid,  
sucrose, talc, and titanium dioxide.  
Ampuls:  1 mL, clear, colorless solution.  
Active Ingredient:  methylergonovine maleate, USP, 0.2 mg.  
Inactive Ingredients:  maleic acid, 0.10 mg; sodium chloride, 7.0 mg; water for injection, qs to 1 mL.  
Chemically, methylergonovine maleate is designated as ergoline­8­carboxamide, 9,10­didehydro­N­[1­
(hydroxymethyl)propyl]­6­methyl­, [8ȕ(S)]­, (Z)­2­butenedioate (1:1) (salt).  
Its structural formula is  
Reference ID: 3150408 
Page 67 of 99

 
 
 
 
CLINICAL PHARMACOLOGY 
Methergine (methylergonovine maleate) acts directly on the smooth muscle of the uterus and increases 
the tone, rate, and amplitude of rhythmic contractions. Thus, it induces a rapid and sustained tetanic 
uterotonic effect which shortens the third stage of labor and reduces blood loss. The onset of action after 
I.V. administration is immediate; after I.M. administration, 2­5 minutes, and after oral administration, 5­
10 minutes. 
Pharmacokinetic studies following an I.V. injection have shown that methylergonovine is rapidly 
distributed from plasma to peripheral tissues within 2­3 minutes or less. The bioavailability after oral 
administration was reported to be about 60% with no accumulation after repeated doses. During 
delivery, with intramuscular injection, bioavailability increased to 78%. Ergot alkaloids are mostly 
eliminated by hepatic metabolism and excretion, and the decrease in bioavailability following oral 
administration is probably a result of first­pass metabolism in the liver. 
Bioavailability studies conducted in fasting healthy female volunteers have shown that oral absorption 
of a 0.2 mg methylergonovine tablet was fairly rapid with a mean peak plasma concentration of 3243 ± 
1308 pg/mL observed at 1.12 ± 0.82 hours. For a 0.2 mg intramuscular injection, a mean peak plasma 
concentration of 5918 ± 1952 pg/mL was observed at 0.41 ± 0.21 hours. The extent of absorption of the 
tablet, based upon methylergonovine plasma concentrations, was found to be equivalent to that of the 
I.M. solution given orally, and the extent of oral absorption of the I.M. solution was proportional to the 
dose following administration of 0.1, 0.2, and 0.4 mg. When given intramuscularly, the extent of 
absorption of Methergine solution was about 25% greater than the tablet. The volume of distribution 
(Vdss/F) of methylergonovine was calculated to be 56.1 ± 17.0 liters, and the plasma clearance (CLp/F) 
was calculated to be 14.4 ± 4.5 liters per hour. The plasma level decline was biphasic with a mean 
elimination half­life of 3.39 hours (range 1.5 to 12.7 hours). A delayed gastrointestinal absorption (T max 
about 3 hours) of Methergine tablet might be observed in postpartum women during continuous 
treatment with this oxytocic agent. 
INDICATIONS AND USAGE 
Following delivery of the placenta, for routine management of uterine atony, hemorrhage and 
subinvolution of the uterus. For control of uterine hemorrhage in the second stage of labor following 
delivery of the anterior shoulder. 
Reference ID: 3150408 
Page 68 of 99

 
   
 
 
CONTRAINDICATIONS 
Hypertension; toxemia; pregnancy; and hypersensitivity. 
WARNINGS 
General 
This drug should not be administered I.V. routinely because of the possibility of inducing sudden 
hypertensive and cerebrovascular accidents. If I.V. administration is considered essential as a lifesaving 
measure, Methergine (methylergonovine maleate) should be given slowly over a period of no less than 
60 seconds with careful monitoring of blood pressure. Intra­arterial or periarterial injection should be 
strictly avoided. 
Caution should be exercised in the presence of impaired hepatic or renal function. 
Breast-feeding  
Mothers should not breast­feed during treatment with Methergine. Milk secreted during this period 
should be discarded. Methergine may produce adverse effects in the breast­feeding infant. Methergine 
may also reduce the yield of breast milk. Mothers should wait at least 12 hours after administration of 
the last dose of Methergine before initiating or resuming breast feeding  
Coronary artery disease  
Patients with coronary artery disease or risk factors for coronary artery disease (e.g., smoking, obesity, 
diabetes, high cholesterol) may be more susceptible to developing myocardial ischemia and infarction 
associated with methylergonovine­induced vasospasm. 
Medication errors 
Inadvertent administration of Methergine to newborn infants has been reported. In these cases of 
inadvertent neonatal exposure, symptoms such as respiratory depression, convulsions, cyanosis and 
oliguria have been reported.  Usual treatment is symptomatic. However, in severe cases, respiratory and 
cardiovascular support is required. 
Methergine has been administered instead of vitamin K and Hepatitis B vaccine, medications which are 
routinely administered to the newborn .  Due to the potential for accidental neonatal exposure, 
Methergine injection should be stored separately from medications intended for neonatal administration. 
PRECAUTIONS 
General 
Caution should be exercised in the presence of sepsis, obliterative vascular disease. Also use with 
caution during the second stage of labor. The necessity for manual removal of a retained placenta should 
occur only rarely with proper technique and adequate allowance of time for its spontaneous separation. 
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Drug Interactions 
CYP 3A4 Inhibitors (e.g., Macrolide Antibiotics and Protease Inhibitors) 
There have been rare reports of serious adverse events in connection with the coadministration of certain 
ergot alkaloid drugs (e.g., dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting 
in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been 
no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be 
coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors 
include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease or reverse 
transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., 
ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with 
caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, 
fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should 
consider the effects on CYP 3A4 of other agents being considered for concomitant use with 
methylergonovine. 
CYP3A4 inducers 
Drugs (e.g. nevirapine, rifampicin) that are strong inducers of CYP3A4 are likely to decrease the 
pharmacological action of Methergine. 
Beta-blockers 
Caution should be exercised when Methergine is used concurrently with beta­blockers. Concomitant 
administration with beta­blockers may enhance the vasoconstrictive action of ergot alkaloids. 
Anesthetics 
Anesthetics like halothan and methoxyfluran may reduce the oxytocic potency of Methergine. 
Glyceryl trinitrate and other antianginal drugs 
Methylergonovine maleate produces vasoconstriction and can be expected to reduce the effect of 
glyceryl trinitrate and other antianginal drugs. 
No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. 
Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with 
other vasoconstrictors, ergot alkaloids, or prostaglandins. 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
No long­term studies have been performed in animals to evaluate carcinogenic potential. The effect of 
the drug on mutagenesis or fertility has not been determined. 
Pregnancy 
Category C. Animal reproductive studies have not been conducted with Methergine. It is also not known 
whether methylergonovine maleate can cause fetal harm or can affect reproductive capacity. Use of 
Methergine  is contraindicated during pregnancy because of its uterotonic effects. (See INDICATIONS 
AND USAGE.) 
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Labor and Delivery 
The uterotonic effect of Methergine is utilized after delivery to assist involution and decrease 
hemorrhage, shortening the third stage of labor. 
Nursing Mothers 
Mothers should not breast­feed during treatment with Methergine and at least 12 hours after 
administration of the last dose. Milk secreted during this period should be discarded. 
Pediatric Use 
Safety and effectiveness in pediatric patients have not been established. 
Geriatric Use 
Clinical studies of Methergine did not include sufficient number of subjects aged 65 and over to 
determine whether they respond differently from younger subjects. Other reported clinical experience 
has not identified differences in response between the elderly and younger patients. In general dose 
selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, 
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant 
disease or other drug therapy. 
ADVERSE REACTIONS 
The most common adverse reaction is hypertension associated in several cases with seizure and/or 
headache. Hypotension has also been reported. Abdominal pain (caused by uterine contractions), nausea 
and vomiting have occurred occasionally. Rarely observed reactions have included: acute myocardial 
infarction, transient chest pains, vasoconstriction, vasospasm, coronary arterial spasm, bradycardia, 
tachycardia, dyspnea, hematuria, thrombophlebitis, water intoxication, hallucinations, leg cramps, 
dizziness, tinnitus, nasal congestion, diarrhea, diaphoresis, palpitation, rash, and foul taste. 1 
There have been rare isolated reports of anaphylaxis, without a proven causal relationship to the drug 
product. 
Postmarketing Experience 
The following adverse drug reactions have been derived from post­marketing experience with 
Methergine via spontaneous case reports. Because these reactions are reported voluntarily from a 
population of uncertain size, it is not possible to reliably estimate their frequency which is therefore 
categorized as not known. 
Nervous system disorders 
Cerebrovascular accident, paraesthesia 
Cardiac disorders 
Ventricular fibrillation, ventricular tachycardia, angina pectoris, atrioventricular block  
DRUG ABUSE AND DEPENDENCE 
Methergine (methylergonovine maleate) has not been associated with drug abuse or dependence of 
either a physical or psychological nature. 
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OVERDOSAGE 
Symptoms of acute overdose may include: nausea, vomiting, oliquria, abdominal pain, numbness, 
tingling of the extremities, rise in blood pressure, in severe cases followed by hypotension, respiratory 
depression, hypothermia, convulsions, and coma. 
Because reports of overdosage with Methergine (methylergonovine maleate) are infrequent, the lethal 
dose in humans has not been established. The oral LD50 (in mg/kg) for the mouse is 187, the rat 93, and 
the rabbit 4.5.2 Several cases of accidental Methergine injection in newborn infants have been reported, 
and in such cases 0.2 mg represents an overdose of great magnitude. However, recovery occurred in all 
but one case following a period of respiratory depression, hypothermia, hypertonicity with jerking 
movements, and convulsions. 
Also, several children 1­3 years of age have accidentally ingested up to 10 tablets (2 mg) with no 
apparent ill effects. A postpartum patient took 4 tablets at one time in error and reported paresthesias and 
clamminess as her only symptoms. 
Treatment of acute overdosage is symptomatic and includes the usual procedures of: 
1. 
removal of offending drug by inducing emesis, gastric lavage, catharsis, and supportive diuresis. 
2. 
maintenance of adequate pulmonary ventilation, especially if convulsions or coma develop. 
3. 
correction of hypotension with pressor drugs as needed. 
4. 
control of convulsions with standard anticonvulsant agents. 
5. 
control of peripheral vasospasm with warmth to the extremities if needed. 3 
DOSAGE AND ADMINISTRATION 
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to 
administration. 
Intramuscularly 
1 mL, 0.2 mg, after delivery of the anterior shoulder, after delivery of the placenta, or during the 
puerperium. May be repeated as required, at intervals of 2­4 hours. 
Intravenously 
1 mL, 0.2 mg, administered slowly over a period of no less than 60 seconds (See WARNINGS.) 
Orally 
One tablet, 0.2 mg, 3 or 4 times daily in the puerperium for a maximum of 1 week. 
HOW SUPPLIED 
Tablets 
0.2 mg round, coated, orchid, branded “78­54” one side, “SANDOZ” other side. 
Bottles of 100…………………………………………………………..NDC 0078­0054­05 
Ampuls 
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1 mL size 
Boxes of 20…………………………………………………………….NDC 0078­0053­03 
Store and Dispense 
Tablets:  Store below 25°C (77°F); in tight, light­resistant container.  
Ampuls:  Store in refrigerator, 2qC­8°C (36°F­46°F). Protect from light. Administer only if solution is 
clear and colorless. 
Distributed by: 
Novartis Pharmaceuticals Corporation 
East Hanover, New Jersey  07936 
© Novartis 
T2012­June 
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Novartis Pharmaceuticals Corporation 
East Hanover, NJ 07936 
IMPORTANT  
DRUG  
WARNING  
RE: MEDICATION ERRORS  RELATED TO  ACCIDENTAL  ADMINISTRATION OF 
METHERGINE® (methylergonovine maleate) INJECTION IN NEWBORN INFANTS 
June 2012 
Dear Healthcare Professional: 
Novartis Pharmaceuticals Corporation (“Novartis”) would  like  to  inform  you  about  medication 
errors  associated  with  the  a c c i d  e n t a l   administration  of  Methergine  injection  in  newborn  
infants.    Methergine  is  used  for    the    prevention    and control of postpartum    hemorrhage. 
Serious adverse outcomes that have been reported 
with inadvertent administration of 
Methergine  to  a  newborn  include  respiratory  depression,  cyanosis,  oliguria,  and  seizures. 
Examples of errors are listed below, 1 
•  Methergine injection intended for the mother has been inadvertently administered to the 
newborn in error. 
•  Methergine injection intended for  the  mother has  been  confused with  routine injectable 
medications  intended  for  the  newborns,  such  as  vitamin  K  injection  and  Hepatitis  B 
vaccine. 
These errors appear to be 1) due to the mother and newborn both being administered medications 
in the same room and/or 2) because the medications can be stored in similar locations such as a 
refrigerator attached to an automatic dispensing machine where medications for the mother and 
newborn are stored together. Therefore, the following recommendations are suggested: 
•  Methergine  injection should be physically  separated  from  other  injectable pediatric 
medications,  such  as  Hepatitis  B  vaccine  and  vitamin  K.  Having  separate  bins  in  one 
refrigerator  may  not  ensure  enough  separation  because  there  is  still  a  possibility  that 
Methergine  injection,  Hepatitis  B  vaccine  or  other  medication  could  be  placed  in  the 
wrong  bin.  Separate refrigerators or  automated dispensing machines for  the  mother and 
newborn medications may be considered, if feasible. 
•  Administering medications to newborn in a setting other than in the mother's room. This 
could  be  a  separate  unit  where  all  routine  newborn  medications  are  administered  or  a 
separate room  on  the  Labor  and  Delivery unit  where  routine  medications for  newborns 
are administered. 
1 Cases have been reported to FDA, Novartis, and Quantros MedMarx 
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Novartis Pharmaceuticals Corporation 
East Hanover, NJ 07936 
Please note that this presentation of the risk profile for Methergine is not comprehensive. Please 
refer  to  the  enclosed  Methergine full  Prescribing  Information for  a  complete  discussion  of  the 
risks associated with Methergine. 
To report adverse events potentially associated   with Methergine,   please   call Novartis 
Pharmaceuticals Corporation at 1-888-NOW-NOVA (1-888-669-6682). 
Alternatively,  adverse  event  information  may  be  reported  to  FDA’s  MedWatch  Reporting 
System by: 
Phone at 1-800-FDA-1088 (1-800-332-1088) 
Facsimile at 1-800-FDA-0178 (1-800-332-0178) 
Mail using FDA Form 3500 located at http://www.fda.gov/medwatch 
Please  contact  Novartis  at  1-888-NOW-NOVA  (1-888-669-6682)  if  you  have  any  questions 
about Methergine or this information. 
Sincerely, 
Enclosure: Methergine – Full Prescribing Information 
Page 2 of 2 
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Hemabate® 
carboprost tromethamine 
injection, USP 
DESCRIPTION 
HEMABATE Sterile Solution, an oxytocic, contains the tromethamine salt of the (15S)­
15 methyl analogue of naturally occurring prostaglandin F2Į in a solution suitable for 
 intramuscular injection. 
Carboprost tromethamine is the established name for the active ingredient in 
HEMABATE. Four other chemical names are: 
1.   (15S)­15­methyl prostaglandin F2Į tromethamine salt 
2.   7­(3Į,5Į­dihydroxy­2ß­[(3S)­3­hydroxy­3­methyl­trans­1­octenyl]­1Į­
cyclopentyl]­cis­5­heptenoic acid compound with 2­amino­2­(hydroxymethyl)­
1,3­propanediol 
3.   (15S)­9Į,11Į,15­trihydroxy­15­methylprosta­cis­5, trans­13­dienoic acid 
tromethamine salt 
4.   (15S)­15­methyl PGF2Į­THAM 
The structural formula is represented below: 
The molecular formula is C25H47O8N. The molecular weight of carboprost tromethamine 
is 489.64. It is a white to slightly off­white crystalline powder. It generally melts between 
95° and 105° C, depending on the rate of heating. 
Carboprost tromethamine dissolves readily in water at room temperature at a 
concentration greater than 75 mg/mL. 
Each mL of HEMABATE Sterile Solution contains carboprost tromethamine equivalent 
to 250 mcg of carboprost, 83 mcg tromethamine, 9 mg sodium chloride, and 9.45 mg 
benzyl alcohol added as preservative. When necessary, pH is adjusted with sodium 
hydroxide and/or hydrochloric acid. The solution is sterile. 
CLINICAL PHARMACOLOGY 
Carboprost tromethamine administered intramuscularly stimulates in the gravid uterus 
myometrial contractions similar to labor contractions at the end of a full term pregnancy. 
Whether or not these contractions result from a direct effect of carboprost on the 
1  
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myometrium has not been determined. Nonetheless, they evacuate the products of 
conception from the uterus in most cases. 
Postpartum, the resultant myometrial contractions provide hemostasis at the site of 
placentation. 
Carboprost tromethamine also stimulates the smooth muscle of the human 
gastrointestinal tract. This activity may produce the vomiting or diarrhea or both that is 
common when carboprost tromethamine is used to terminate pregnancy and for use 
postpartum. In laboratory animals and also in humans carboprost tromethamine can 
elevate body temperature. With the clinical doses of carboprost tromethamine used for 
the termination of pregnancy, and for use postpartum, some patients do experience 
transient temperature increases. 
In laboratory animals and in humans large doses of carboprost tromethamine can raise 
blood pressure, probably by contracting the vascular smooth muscle. With the doses of 
carboprost tromethamine used for terminating pregnancy, this effect has not been 
clinically significant. In laboratory animals and also in humans carboprost tromethamine 
can elevate body temperature. With the clinical doses of carboprost tromethamine used 
for the termination of pregnancy, some patients do experience temperature increases. In 
some patients, carboprost tromethamine may cause transient bronchoconstriction. 
Drug plasma concentrations were determined by radioimmunoassay in peripheral blood 
samples collected by different investigators from 10 patients undergoing abortion. The 
patients had been injected intramuscularly with 250 micrograms of carboprost at two 
hour intervals. Blood levels of drug peaked at an average of 2060 picograms/mL one­half 
hour after the first injection then declined to an average concentration of 770 
picograms/mL two hours after the first injection just before the second injection. The 
average plasma concentration one­half hour after the second injection was slightly higher 
(2663 picograms/mL) than that after the first injection and decreased again to an average 
of 1047 picograms/mL by two hours after the second injection. Plasma samples were 
collected from 5 of these 10 patients following additional injections of the prostaglandin. 
The average peak concentrations of drug were slightly higher following each successive 
injection of the prostaglandin, but always decreased to levels less than the preceding peak 
values by two hours after each injection. 
Five women who had delivery spontaneously at term were treated immediately 
postpartum with a single injection of 250 micrograms of carboprost tromethamine. 
Peripheral blood samples were collected at several times during the four hours following 
treatment and carboprost tromethamine levels were determined by radioimmunoassay. 
The highest concentration of carboprost tromethamine was observed at 15 minutes in two 
patients (3009 and 2916 picograms/mL), at 30 minutes in two patients (3097 and 2792 
picograms/mL), and at 60 minutes in one patient (2718 picograms/mL). 
INDICATIONS AND USAGE 
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HEMABATE Sterile Solution is indicated for aborting pregnancy between the 13th and 
20th weeks of gestation as calculated from the first day of the last normal menstrual 
period and in the following conditions related to second trimester abortion: 
1.   Failure of expulsion of the fetus during the course of treatment by another  
method;  
2.   Premature rupture of membranes in intrauterine methods with loss of drug and 
insufficient or absent uterine activity; 
3.   Requirement of a repeat intrauterine instillation of drug for expulsion of the fetus; 
4.   Inadvertent or spontaneous rupture of membranes in the presence of a previable 
fetus and absence of adequate activity for expulsion. 
HEMABATE is indicated for the treatment of postpartum hemorrhage due to uterine 
atony which has not responded to conventional methods of management. Prior treatment 
should include the use of intravenously administered oxytocin, manipulative techniques 
such as uterine massage and, unless contraindicated, intramuscular ergot preparations. 
Studies have shown that in such cases, the use of HEMABATE has resulted in 
satisfactory control of hemorrhage, although it is unclear whether or not ongoing or 
delayed effects of previously administered ecbolic agents have contributed to the 
outcome. In a high proportion of cases, HEMABATE used in this manner has resulted in 
the cessation of life threatening bleeding and the avoidance of emergency surgical 
intervention. 
CONTRAINDICATIONS 
1.   Hypersensitivity (including anaphylaxis and angioedema) to HEMABATE Sterile 
Solution [see ADVERSE REACTIONS, Post-marketing Experience] 
2.   Acute pelvic inflammatory disease 
3.   Patients with active cardiac, pulmonary, renal or hepatic disease 
WARNINGS 
HEMABATE Sterile Solution (carboprost tromethamine), like other potent oxytocic 
agents, should be used only with strict adherence to recommended dosages. 
HEMABATE should be used by medically trained personnel in a hospital which can 
provide immediate intensive care and acute surgical facilities. 
HEMABATE does not appear to directly affect the fetoplacental unit. Therefore, the 
possibility does exist that the previable fetus aborted by HEMABATE could exhibit 
transient life signs. HEMABATE is not indicated if the fetus in utero has reached the 
stage of viability. HEMABATE should not be considered a feticidal agent. 
Evidence from animal studies has suggested that certain other prostaglandins have some 
teratogenic potential. Although these studies do not indicate that HEMABATE is 
3  
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teratogenic, any pregnancy termination with HEMABATE that fails should be completed 
by some other means. 
This product contains benzyl alcohol. Benzyl alcohol has been reported to be associated 
with a fatal "Gasping Syndrome" in premature infants. 
PRECAUTIONS 
General 
Animal studies lasting several weeks at high doses have shown that prostaglandins of the 
E and F series can induce proliferation of bone. Such effects have also been noted in 
newborn infants who have received prostaglandin E1 during prolonged treatment. There 
is no evidence that short term administration of HEMABATE Sterile Solution can cause 
similar bone effects. 
In patients with a history of asthma, hypo­ or hypertension, cardiovascular, renal, or 
hepatic disease, anemia, jaundice, diabetes, or epilepsy, HEMABATE should be used 
cautiously. 
As with any oxytocic agent, HEMABATE should be used with caution in patients with 
compromised (scarred) uteri. 
Abortion 
As with spontaneous abortion, a process which is sometimes incomplete, abortion 
induced by HEMABATE may be expected to be incomplete in about 20% of cases. 
Although the incidence of cervical trauma is extremely small, the cervix should always 
be carefully examined immediately post­abortion. 
Use of HEMABATE is associated with transient pyrexia that may be due to its effect on 
hypothalamic thermoregulation. Temperature elevations exceeding 2° F (1.1° C) were 
observed in approximately one­eighth of the patients who received the recommended 
dosage regimen. In all cases, temperature returned to normal when therapy ended. 
Differentiation of post­abortion endometritis from drug­induced temperature elevations is 
difficult, but with increasing clinical experience, the distinctions become more obvious 
and are summarized below: 
Endometritis 
Pyrexia induced by 
pyrexia 
HEMABATE 
1.  Time of onset: Typically, on third post­
Within 1 to 16 hours after the first 
abortional day (38° C or higher). 
injection. 
2.  Duration: Untreated pyrexia and 
Temperatures revert to pretreatment 
infection continue and may give rise to 
levels after discontinuation of therapy 
other pelvic infections. 
without any other treatment. 
3.  Retention: Products of conception are 
Temperature elevation occurs whether or 
often retained in the cervical os or 
not tissue is retained. 
uterine cavity. 
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4.  Histology: Endometrium is infiltrated 
Although the endometrial stroma may be 
with lymphocytes and some areas are 
edematous and vascular, it is not 
necrotic and hemorrhagic.  
inflamed. 
5.  The uterus: Often remains boggy and 
Uterine involution normal and uterus is 
soft with tenderness over the fundus, 
not tender. 
and pain on moving the cervix on 
bimanual examination. 
6.  Discharge: Often associated with foul­
Lochia normal. 
smelling lochia and leukorrhea. 
7.  Cervical culture: The culture of pathological organisms from the cervix or uterine 
cavity after abortion alone does not warrant the diagnosis of septic abortion in the 
absence of clinical evidence of sepsis. Pathogens have been cultured soon after 
abortion in patients with no infections. Persistent positive culture with clear clinical 
signs of infections are significant in the differential diagnosis. 
8.  Blood count: Leukocytosis and differential white cell counts do not distinguish 
between endometritis and hyperthermia caused by HEMABATE since total WBC’s 
may increase during infection and transient leukocytosis may also be drug­induced. 
Fluids should be forced in patients with drug­induced fever and no clinical or 
bacteriological evidence of intrauterine infection. Any other simple empirical 
measures for temperature reduction are unnecessary because all fevers induced by 
HEMABATE have been transient or self­limiting.  
Postpartum Hemorrhage 
Increased blood pressure. In the postpartum hemorrhage series, 5/115 (4%) of patients 
had an increase of blood pressure reported as a side effect. The degree of hypertension 
was moderate and it is not certain as to whether this was in fact due to a direct effect of 
HEMABATE or a return to a status of pregnancy associated hypertension manifest by the 
correction of hypovolemic shock. In any event the cases reported did not require specific 
therapy for the elevated blood pressure. 
Use in patients with chorioamnionitis. During the clinical trials with HEMABATE, 
chorioamnionitis was identified as a complication contributing to postpartum uterine 
atony and hemorrhage in 8/115 (7%) of cases, 3 of which failed to respond to 
HEMABATE. This complication during labor may have an inhibitory effect on the 
uterine response to HEMABATE similar to what has been reported for other oxytocic 
agents.1 
Drug Interactions 
HEMABATE may augment the activity of other oxytocic agents. Concomitant use with 
other oxytocic agents is not recommended. 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenic bioassay studies have not been conducted in animals with HEMABATE 
due to the limited indications for use and short duration of administration. No evidence of 
mutagenicity was observed in the Micronucleus Test or Ames Assay. 
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Pregnancy: Teratogenic Effects: Pregnancy Category C 
Animal studies do not indicate that HEMABATE is teratogenic, however, it has been 
shown to be embryotoxic in rats and rabbits and any dose which produces increased 
uterine tone could put the embryo or fetus at risk. 
Pediatric Use 
Safety and effectiveness in pediatric patients have not been established. 
ADVERSE REACTIONS 
The adverse effects of HEMABATE Sterile Solution are generally transient and 
reversible when therapy ends. The most frequent adverse reactions observed are related 
to its contractile effect on smooth muscle. 
In patients studied, approximately two­thirds experienced vomiting and diarrhea, 
approximately one­third had nausea, one­eighth had a temperature increase greater than 
2° F, and one­fourteenth experienced flushing. 
The pretreatment or concurrent administration of antiemetic and antidiarrheal drugs 
decreases considerably the very high incidence of gastrointestinal effects common with 
all prostaglandins used for abortion. Their use should be considered an integral part of the 
management of patients undergoing abortion with HEMABATE. 
Of those patients experiencing a temperature elevation, approximately one­sixteenth had 
a clinical diagnosis of endometritis. The remaining temperature elevations returned to 
normal within several hours after the last injection. 
Adverse effects observed during the use of HEMABATE for abortion and for 
hemorrhage, not all of which are clearly drug related, in decreasing order of frequency 
include: 
Vomiting 
Nervousness 
Diarrhea 
Nosebleed 
Nausea 
Sleep disorders 
Flushing or hot flashes 
Dyspnea 
Chills or shivering 
Tightness in chest 
Coughing 
Wheezing 
Headaches 
Posterior cervical 
Endometritis 
perforation 
Hiccough 
Weakness 
Dysmenorrhea­like 
Diaphoresis 
pain 
Dizziness 
Paresthesia 
Blurred vision 
Backache 
Epigastric pain 
Muscular pain 
Excessive thirst 
Breast tenderness 
Twitching eyelids 
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Eye pain 
Gagging, retching 
Drowsiness 
Dry throat 
Dystonia 
Sensation of choking 
Asthma 
Thyroid storm 
Injection site pain 
Syncope 
Tinnitus 
Palpitations 
Vertigo 
Rash 
Vaso­vagal syndrome 
Upper respiratory 
Dryness of mouth 
infection 
Hyperventilation 
Leg cramps 
Respiratory distress 
Perforated uterus 
Hematemesis 
Anxiety 
Taste alterations 
Chest pain 
Urinary tract infection 
Retained placental 
Septic shock 
   fragment 
Torticollis 
Shortness of breath 
Lethargy 
Fullness of throat 
Hypertension 
Uterine sacculation 
Tachycardia 
Faintness, light­ 
Pulmonary edema 
headedness 
Endometritis from 
Uterine rupture 
IUCD 
The most common complications when HEMABATE was utilized for abortion requiring 
additional treatment after discharge from the hospital were endometritis, retained 
placental fragments, and excessive uterine bleeding, occurring in about one in every 50 
patients. 
Post­marketing experience: 
Hypersensitivity reactions (e.g. Anaphylactic reaction, Anaphylactic shock, 
Anaphylactoid reaction, Angioedema). 
DOSAGE AND ADMINISTRATION 
1. Abortion and Indications 1–4 
An initial dose of 1 mL of HEMABATE Sterile Solution (containing the equivalent of 
250 micrograms of carboprost) is to be administered deep in the muscle with a tuberculin 
syringe. Subsequent doses of 250 micrograms should be administered at 1½ to 3½ hour 
intervals depending on uterine response. 
An optional test dose of 100 micrograms (0.4 mL) may be administered initially. The 
dose may be increased to 500 micrograms (2 mL) if uterine contractility is judged to be 
inadequate after several doses of 250 micrograms (1 mL). 
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The total dose administered of carboprost tromethamine should not exceed 12 milligrams 
and continuous administration of the drug for more than two days is not recommended. 
2. For Refractory Postpartum Uterine Bleeding: 
An initial dose of 250 micrograms of HEMABATE Sterile Solution (1 mL of 
HEMABATE) is to be given deep, intramuscularly. In clinical trials it was found that the 
majority of successful cases (73%) responded to single injections. In some selected cases, 
however, multiple dosing at intervals of 15 to 90 minutes was carried out with successful 
outcome. The need for additional injections and the interval at which these should be 
given can be determined only by the attending physicians as dictated by the course of 
clinical events. The total dose of HEMABATE should not exceed 2 milligrams (8 doses). 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 
HOW SUPPLIED 
HEMABATE Sterile Solution is available in the following packages: 
1 mL ampoules  
NDC 0009­0856­05 
10 x 1 mL ampoules  
NDC 0009­0856­08 
Each mL of HEMABATE contains carboprost tromethamine equivalent to 250 mcg of 
carboprost. 
HEMABATE must be refrigerated at 2° to 8° C (36° to 46° F). 
1Duff, Sanders, and Gibbs; The course of labor in term patients with chorioamnionitis; 
Am. J. Obstet. Gynecol.; vol. 147, no. 4, October 15, 1983 pp 391–395. 
This product’s label may have been updated. For current full prescribing information, 
please visit www.pfizer.com 
Rx only 
LAB­0032­5.0 
Revised December 2013 
Reference ID: 3420404 
8 
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PARTNERS HUMAN RESEARCH COMMITTEE
PROTOCOL SUMMARY
Partners Human Subjects Research Application Form
Filename: Protocol Summary
Version Date:  October 15, 2014
 
1
Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank.
PRINCIPAL/OVERALL INVESTIGATOR
Jimin Kim, MD
PROTOCOL TITLE
Second-line Uterotonics in Postpartum Hemorrhage: A Randomized Clinical 
Trial
FUNDING
n.a.
VERSION DATE
04/19/2022
SPECIFIC AIMS
Concisely state the objectives of the study and the hypothesis being tested.
The purpose of this study is to prospectively compare the efficacy of the two 
most commonly used second-line uterotonic agents in postpartum 
hemorrhage (PPH): methylergonovine maleate (methylergonovine) and 15-
methyl prostaglandin F2α (carboprost). Study participants with abnormal 
bleeding immediately post-cesarean delivery will receive, upon request, 
methergine and/or carboprost in a randomized fashion after oxytocin. The 
choice of carboprost or methylergonovine as the first additional uterotonic to 
be administered will be randomized and all members of the care team will be 
blinded to the randomization. Dosing and timing of the uterotonics will be 
unaltered from standard of care. Uterine tone score, blood loss, need for 
additional uterotonics, need for transfusion and interventions to control 
bleeding will be recorded. We hypothesize that patients receiving 
methylergonovine will have a 1-point greater reduction in uterine tone (on a 
0-10 scale) at 10 minutes after administration compared to carboprost.
BACKGROUND AND SIGNIFICANCE
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
Primary PPH is defined by the American College of Obstetricians and 
Gynecologists as a cumulative blood loss >1000 mL or blood loss 
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accompanied by signs of hypovolemia within 24 hours of delivery. It remains 
the leading source of maternal morbidity and mortality worldwide with 
uterine atony identified as the underlying cause in up to 80% of cases 
[Combs et al. Obstet Gynecol 1991;77:69–76. Dildy GA. Clin Obstet 
Gynecol. 2002; 45(2): 330-44]. Oxytocin is routinely administered 
prophylactically during the third stage of labor to decrease the risk of PPH 
[Westhoff et al. Cochrane Database Syst Rev 2013; 10:CD001808], and it is 
considered the first-line medical treatment for PPH. When postpartum 
bleeding persists, a multidisciplinary approach combining mechanical, 
pharmacologic, and surgical measures is indicated. The most effective 
second-line uterotonic agent remains unknown and a lack of consensus 
exists regarding the best pharmacologic management of PPH. 
Recent literature indicates that methylergonovine may be superior to 
carboprost in the treatment of PPH [Butwick et al. AJOG 2015], but due to 
the unpredictable and emergent nature of PPH, high quality evidence of their 
comparative efficacy is scarce. This study will be the first to prospectively 
compare the two agents in a randomized fashion thereby allowing for direct 
comparison of their efficacy.
RESEARCH DESIGN AND METHODS
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be enrolled 
by researchers study-wide and by Partners researchers.  Provide a brief summary of the 
eligibility criteria (for example, age range, gender, medical condition).  Include any local site 
restrictions, for example, “Enrollment at Partners will be limited to adults although the sponsor’s 
protocol is open to both children and adults.”
The study will be conducted as a randomized, double blinded prospective 
trial. All patients of participating obstetricians will initially be given a 
standard information packet from their obstetrician’s office at their 28-week 
visit. The packet will contain basic information regarding their delivery as 
well as a copy of the study Consent Form and a Flier outlining this study’s 
goals and methods. Patients meeting eligibility criteria who plan vaginal or 
cesarean delivery and have reach 37 weeks gestation or greater, will be 
asked by their obstetrician for permission to be contacted by a study co-
investigator by email. Those patients who are willing to be contacted will be 
sent an email reminding them of the study with a copy of the Study Flier and 
Consent Form attached to the email.
Eligibility criteria will include all female patients ages 18-50 with delivery of 
a viable fetus (24 weeks gestation or above) by non-emergent cesarean 
section (C/S) who experience abnormal immediate postpartum bleeding.
Exclusion criteria for enrollment in the study will include non-English 
speaking patients requiring an interpreter who are undergoing urgent, non-
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scheduled C/S, patients with pre-existing systemic hypertension (HTN) or 
any hypertensive disorder of pregnancy, patients with cardiovascular 
disease, patients with asthma, patients who refuse to accept blood 
transfusion (e.g. Jehovah’s Witnesses), patients with a known coagulopathy 
or abnormal baseline coagulation profile, patients with known or suspected 
hypersensitivity to either of the two study drugs, and patients with known or 
suspected delayed PPH after leaving the operating room from the cesarean 
delivery.
We anticipate enrolling 1250 patients in order to randomizing a total of 100 
patients for this study, based on a calculation for 80% power to detect a 
mean difference of uterine tone score as small as 1.2 using a two-tailed two-
sample t test, assuming a standard deviation of 1.9 and significant level at 
0.05.
Patients will be recruited from those who deliver by cesarean section at the 
Brigham and Women’s Hospital.
Briefly describe study procedures.  Include any local site restrictions, for example, “Subjects 
enrolled at Partners will not participate in the pharmacokinetic portion of the study.”  Describe 
study endpoints.
Parturients will be assessed for eligibility using a pre-screening questionnaire 
at the time of admission to the Labor and Delivery (L&D) unit. Eligible 
patients will be given the opportunity to consent to participate in the study 
at the time of admission to the labor and delivery unit, or at the time of 
consent for elective cesarean section. Emergent cesarean section deliveries 
will be excluded. 
Participants will receive standard care in terms of all medical and surgical 
interventions to manage postpartum bleeding. This will include a standard 
infusion of oxytocin immediately postpartum. If a second-line uterotonic is 
requested after oxytocin, the patient will be randomized by the 
anesthesiologist to either the “methylergonovine” or “carboprost” study 
group using a computer-generated randomization scheme printed on a piece 
of paper (called the Randomization sheet) in a sealed envelope. The 
anesthesiologist will document the patient MRN and study ID number on this 
Randomization Sheet and then return it to the envelope. The envelope will 
also contain a Uterine Tone Score Intraop Data Collection Sheet for 
documentation of the primary outcome as well as additional information, as 
described below.
Participants will receive either methylergonovine or carboprost depending on 
their randomization. The anesthesiologist will withdraw the appointed 
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medication (based on subject randomization) from the O.R. omnicell and 
administer it without revealing to anyone in the O.R. which drug was given. 
They will document the medication in the subject’s Epic record in the usual 
fashion. Obstetricians and nursing staff are not able to view the Epic 
anesthesia record in real time, and therefore will not be able to see which 
medication was given by the anesthesiologist. Every effort will be made to 
avoid having the physician co-investigator be involved in the patient’s care. 
Occasionally, though, if staffing is limited or there is high clinical acuity in 
the subject’s case (e.g. massive postpartum hemorrhage), the 
anesthesiologist co-investigator who consented the patient may need to be 
involved in helping with the patient’s intraoperative care. If this is the case, 
coercion will be avoided since the patient consent will occur first, and the 
study investigator will only become the patient’s physician after the informed 
consenting process is complete. Patients, obstetricians, study co-
investigators and nurses will be blinded to the study group assignment but 
the anesthesiologist will be unblinded to study randomization and the 
identity of each drug being given.
At the time of administration of the first study drug, the anesthesiologist will 
ask the obstetrician to rate the uterine tone on a scale of 0 to 10 (0 being 
‘no tone’, 10 being ‘excellent tone’). The anesthesiologist will then set a 
timer. After administration of the study drug, patients will receive our usual 
standard of care. At 5 minutes and again at 10 minutes from the onset of 
timing, the anesthesiologist will once again ask the obstetrician for a rating 
of uterine tone between 0 and 10. These values will be recorded by the 
anesthesiologist on the Uterine Tone Score Intraop Data Collection sheet 
provided in the envelope with the Randomization sheet by the investigator.
If a third uterotonic is desired (after oxytocin and the initial study drug), the 
patient will receive the alternate drug (methylergonovine or carboprost), 
prepared by the unblinded anesthesiologist. Any additional measures for 
postpartum bleeding will be provided in the usual fashion as standard of 
care.
At the end of the C/S, the anesthesiologist will return the Randomization 
sheet and the Uterine Tone Score Intraop Data Collection sheet in the 
previously sealed envelope to a folder where all paper documents for the 
study are temporarily stored in a locked room on the L&D floor. On each day 
of subject enrollment, the unblinded principal investigator will collect the 
envelope with the Randomization sheet and Uterine Tone Score Intraop Data 
Collection sheet and transfer it to a locked filing cabinet in a locked office to 
which only the principal investigator has access. 
After the subject has recovered on the L&D floor and is ready for transfer to 
the postpartum floor, a blinded study co-investigator will interview the 
patient by phone (to limit physical contact, due to COVID-19 precautions) 
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using the ‘2-4 Hour Interview Guide’. At 18-24 hours postpartum, the 
subject will again be interviewed by phone by a blinded study co-
investigator, using the ’18-24 Hour Interview Guide’. Both postpartum 
interview guides will contain the same content, allowing for subjective 
adverse effects to be accurately assessed at 2 timepoints. (no later than 24 
hours after delivery). This data will be documented on the 2-4 Hour and 18-
24 Hour Interview Guides, to be retrieved by the principal investigator (who 
is not blinded) after the day of subject enrollment, then stored in the locked 
office, and ultimately entered into a secure electronic database, REDCap, by 
a blinded study investigator. This will allow them to assess for any subjective 
side effects of the study medication, as listed below (Secondary Endpoint 
#9). 
An unblinded study investigator not involved in data collection and with 
access to REDCap will be responsible for collecting all primary and secondary 
outcomes (including side-effects of study medications) from the Uterine 
Tone Score Intraop Data Collection sheet, the Pre Transfer Interview Guide 
and Epic medical records onto the Second Line Uterotonics Data Collection 
Sheet and entering this information into REDCap. Subject randomization, 
patient MRN and the linked study ID number will be documented on a 
separate form in the REDCap database by the unblinded principal 
investigator, to preserve the integrity of the data collection and entry.
Study endpoints will be:
Primary Endpoint
1. Uterine tone score as recorded at 10 minutes following the 
administration of the second-line uterotonic.
Secondary Endpoints
1. Uterine tone score recorded at 5 minutes following the administration 
of the second-line uterotonic.
2. Need for an additional uterotonic agent after the study drug
3. Number of units of blood products transfused (t0 = time of delivery; 
tfinal = 24 hours after delivery)
4. Need for a surgical or radiologic intervention to control bleeding
5. Quantitative intrapartum blood loss 
6. Pre- vs post-delivery hematocrit values
7. Maternal morbidity: vasopressor requirement or hypovolemic shock, 
admission to the intensive care unit postpartum, mechanical 
ventilation, hypertensive emergency, myocardial ischemia, acute 
kidney injury, acute lung injury or circulatory overloard from blood 
transfusion, allergic reaction deemed the result of blood transfusion, 
hypovolemic shock, or vasopressor requirement.
8. Length of postoperative hospital stay
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9. Medication side effects within 2 hrs postpartum: nausea, vomiting or 
diarrhea, abdominal pain, shortness of breath, headache, blurred 
vision, anxiety, chest pain, sweating, palpitations 
For studies involving treatment or diagnosis, provide information about standard of care at 
Partners (e.g., BWH, MGH) and indicate how the study procedures differ from standard care.  
Provide information on available alternative treatments, procedures, or methods of diagnosis.
All patients undergoing a C/S delivery at the Brigham and Women’s Hospital 
(BWH) have a peripheral IV and baseline laboratory work on admission to 
the labor and delivery floor. The standard of care at BWH for women 
undergoing C/S includes spinal anesthesia with bupivacaine, fentanyl, and 
morphine, as will be used in this study unless contraindicated. The overall 
anesthetic management of a patient in the operating room will be at the 
discretion of the anesthesia attending physician, including crystalloid fluid 
administered, anti-emetic medication, analgesic medication and 
vasopressors used. Blood products transfused will be at the discretion of the 
attending physicians.
At the time of C/S and clamping of the umbilical cord, a standard infusion of 
oxytocin 30U/500mL is begun at a rate of 15-30U/hr. If uterine tone is 
perceived to be inadequate, this rate may be increased and the obstetrician 
may attempt maneouvers to improve uterine tone. Additionally, at this time 
a second-line uterotonic is typically requested.
The choice of whether to give methylergonovine or carboprost as a second-
line uterotonic depends primarily on provider preference and the presence of 
any medical contraindications. Methylergonovine must be avoided in patients 
at risk for hypertension; carboprost should be avoided in those with current 
reactive airway disease. If the second-line agent is unsuccessful in curbing 
the bleeding, the alternate agent is given. Carboprost may be re-
administered as often as every 15 minutes; methylergonovine every 4 
hours. 
Further escalation in treatment involves medical and surgical measures, 
such as cytotec (misoprostol), intrauterine vasopressin injection, uterine 
massage, intrauterine balloon tamponade, occlusion of pelvic arteries, B-
lynch sutures, or hysterectomy. In this study, patients will have the 
opportunity to receive one or both of the second-line agents, as well as all 
other standard measures for PPH management; however the choice of 
uterotonic that is given first will be randomized.
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Describe how risks to subjects are minimized, for example, by using procedures which are 
consistent with sound research design and which do not unnecessarily expose subjects to risk or 
by using procedures already being performed on the subject for diagnostic or treatment purposes.
This study is designed as a double blinded, randomized study. 
Several national and international guidelines have recommended both drugs 
as second-line uterotonics to treat PPH, but there is no evidence to specify 
which should be used first, or which might be more effective. Therefore, by 
giving the patients the opportunity to receive both drugs, any deviation from 
standard practice and risk to the patients will be minimized.
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective criteria for 
removing a subject from the study, for example, objective criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events.  The inclusion of objective drop criteria is 
especially important in studies designed with placebo control groups.
All participants will be under the direct care of an obstetric anesthesiologist, 
obstetrician, and a labor and delivery nurse throughout the course of the 
study. Standard care will be employed for every patient with the exception 
of the randomization of the order in which they receive their second-line 
uterotonic agents. At all times, providers’ clinical assessment of the patient 
will be paramount in guiding decision-making. Providers will have full ability 
to exercise their best judgement in taking care of the patient. If this results 
in a decision to deviate from the study protocol, the patient will be cared for 
according to the providers’ discretion. If the practice deviates from the study 
protocol, the patient will be withdrawn from the study thereafter.
Patients will be monitored carefully by their anesthesia and obstetric 
providers for any potential side-effects of the medications they receive in the 
study. 
The principal investigator will additionally review all data collection and 
recruitment on every 5th patient recruited and immediately as needed if a 
concern arises. At the time of each review point, the principal investigator 
will review all forms and data entry to ensure completeness, accuracy, and 
adherence to the protocol.  Any concern for adverse events will result in 
immediate review by the principal investigator with the study being 
temporarily halted, and the events will be reported to the IRB and the PHRC 
in accordance with the PHRC Policy on Unanticipated Problems Involving 
Risks to Subjects or Others, including Adverse Events. The principal 
investigator will be primarily responsible for deciding if the study needs to be 
stopped, but this can also be decided by any of the study co-investigators.
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FORESEEABLE RISKS AND DISCOMFORTS
Provide a brief description of any foreseeable risks and discomforts to subjects.  Include those 
related to drugs/devices/procedures being studied and/or administered/performed solely for 
research purposes.  In addition, include psychosocial risks, and risks related to privacy and 
confidentiality.  When applicable, describe risks to a developing fetus or nursing infant.
As described above, all patients will be treated with the standard of care and 
should therefore not be exposed to any additional risk or discomfort. As is 
typical practice, all patients will receive an intravenous (IV) line and baseline 
labs on admission to the L&D floor, and oxytocin will be given immediately 
after the baby is delivered and the cord clamped. Thereafter, patients will 
receive all usual measures to manage postpartum bleeding, including, but 
not limited to, administration of additional uterotonics, uterine massage, 
additional diagnostic lab values and resuscitative measures. Second-line 
uterotonics will be given as per study protocol, with additional uterotonics as 
per clinical assessment.
After the delivery, the patient will be monitored on the labor and delivery 
floor for several hours postoperatively before discharge to the postpartum 
recovery unit, as is customary.
Only clinical providers will be involved in the care of the patient. Study staff 
will be involved in consent and collection of data points during enrollment, 
but they will not participate directly in patient care. Privacy and 
confidentiality will be maintained as per HIPAA standards.
 
EXPECTED BENEFITS
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study.  Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.”  
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances.
The incidence of PPH is on the rise in the U.S.A., with uterine atony the main 
etiology. Oxytocin is given prophylactically in cesarean section deliveries, but 
when it is inadequate, second-line agents are required. While recent 
literature suggests methylergonovine may be more effective than carboprost 
for PPH treatment, no prospective data exists comparing the two. This study 
may yield new information demonstrating the comparative efficacy of these 
two drugs. This could guide future practice in determining which second-line 
agent is preferred for PPH management. In turn, this could allow future 
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patients to benefit from decreased morbidity and mortality associated with 
hemorrhage and transfusion.
EQUITABLE SELECTION OF SUBJECTS
The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so.  Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research.
All English-speaking patients undergoing non-emergent urgent C/S at the 
Brigham and Women’s Hospital and all English or non-English speaking 
patients undergoing scheduled C/S will be eligible for participation except 
those with a known coagulopathy or high risk for coagulopathy (as this 
might alter the management of bleeding beyond standard measures) as well 
as those with contraindications to either study drug, i.e. HTN or active 
asthma (with use of a bronchodilator in the past 24 months) or documented 
allergy to either drug. Patients refusing to receive blood products due to 
religious beliefs will also be excluded. 
Patients experiencing uterine atony requiring an additional, second-line 
uterotonic agent after C/S will be randomized to participate in this study, as 
a result, those who participate will be of the same population that will 
benefit from this research.
When people who do not speak English are excluded from participation in the research, provide 
the scientific rationale for doing so.  Individuals who do not speak English should not be denied 
participation in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present.
Non-English speaking patients who are undergoing unscheduled, urgent C/S 
will not be enrolled due to the potentially stressful or urgent nature of all C/S 
in patients who have failed to deliver in labor. In such cases, there may not 
be time to adequately obtain informed consent for participation in the study 
without hindering clinical care. Therefore the study will only enroll urgent 
C/S patients who speak English and are able to provide informed consent 
without the aid of an interpreter. Patients undergoing routine, schedule C/S 
may be English-speaking or non-English speaking, since there will be no 
undue stress involved preoperatively and there will be ample opportunity for 
full consent in the patient’s first language with the aid of an official in-person 
interpreter.
For guidance, refer to the following Partners policy:
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          Obtaining and Documenting Informed Consent of Subjects who do not Speak English
          https://partnershealthcare-public.sharepoint.com/ClinicalResearch/Non-
English_Speaking_Subjects.1.10.pdf
RECRUITMENT PROCEDURES
Explain in detail the specific methodology that will be used to recruit subjects.  Specifically 
address how, when, where and by whom subjects will be identified and approached about 
participation.  Include any specific recruitment methods used to enhance recruitment of women 
and minorities.
Eligible patients undergoing a scheduled C/S or non-emergent C/S after 
labor will be provided with the study Flier regarding the study and the study 
consent form by a study physician investigator or research assistant when 
they are admitted to the L&D floor. The person will not be directly involved 
in the care of the patient. Patients will only be approached in their rooms by 
a study physician to obtain their informed consent. The study physician will 
follow all institutional policies and contact isolation level safety procedures to 
minimize risks to the patient of possible COVID-19 exposure. They will 
maintain a 6-foot distance from the patient as much as possible. There will 
be minimal shared points of contact between study staff and patient, (such 
as the consent form, clipboard, or pen). Proper hand hygiene and 
replacement of PPE will be performed throughout as necessary. 
At this time, patients will have the opportunity to ask any questions they 
may have regarding the study and to opt in or out as desired through 
conversation with the physician study investigator. During this conversation, 
the purpose of the study and scope of participation will be discussed. If the 
patient is agreeable to participation, written consent will be obtained by the 
physician study investigator. If the patient is non-English speaking, the 
services of an in-person interpreter will be obtained for the conversation 
with the study investigator.
Provide details of remuneration, when applicable.  Even when subjects may derive medical 
benefit from participation, it is often the case that extra hospital visits, meals at the hospital, 
parking fees or other inconveniences will result in additional out-of-pocket expenses related to 
study participation.  Investigators may wish to consider providing reimbursement for such 
expenses when funding is available
No remuneration will be provided for participation in this study.
For guidance, refer to the following Partners policies:
          Recruitment of Research Subjects 
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          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Recruitment_Of_Research_Subjects.pdf
          Guidelines for Advertisements for Recruiting Subjects
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Guidelines_For_Advertisements.1.11.pdf
          Remuneration for Research Subjects
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Remuneration_for_Research_Subjects.pdf
CONSENT PROCEDURES
Explain in detail how, when, where, and by whom consent is obtained, and the timing of consent 
(i.e., how long subjects will be given to consider participation).  For most studies involving more 
than minimal risk and all studies involving investigational drugs/devices, a licensed physician 
investigator must obtain informed consent.  When subjects are to be enrolled from among the 
investigators’ own patients, describe how the potential for coercion will be avoided.
All pregnant women receiving care from participating obstetricians will 
receive an initial informational study Flier and consent form in their 28-wk 
prenatal information package from the obstetrician’s office. 
Upon admission to the L&D unit, all potentially eligible patients will be pre-
screened using the OB Pre-Screen Questionnaire for 2nd Line Uterotonics 
Study. Those who meet eligibility criteria will, once again, receive the study 
Flier and consent form. A physician study investigator who is not involved in 
their care at the time of consent will review and discuss the study plan at 
this time, allowing subjects the opportunity to ask questions and address 
any of their concerns or any issues surrounding the study. Subjects 
interested in participating will then be consented by the physician 
investigator and enrolled in the study. An official in-person interpreter fluent 
in the patient’s native language will be used to translate an oral version of 
the English consent form in the patient’s native language. Social distancing 
will be maintained during all in-person conversations and appropriate PPE 
will be worn by any staff during these conversations. The patient will be 
allowed to keep the pen they use to sign the consent form, in order to 
minimize sharing of physical items, and lower the risk for COVID-19 
transmission.
 
NOTE: When subjects are unable to give consent due to age (minors) or impaired decision-
making capacity, complete the forms for Research Involving Children as Subjects of Research 
and/or Research Involving Individuals with Impaired Decision-making Capacity, available on 
the New Submissions page on the PHRC website: 
      https://partnershealthcare.sharepoint.com/sites/phrmApply/aieipa/irb
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For guidance, refer to the following Partners policy:
     Informed Consent of Research Subjects:
     https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Informed_Consent_of_Research_Subjects.pdf
DATA AND SAFETY MONITORING
Describe the plan for monitoring the data to ensure the safety of subjects.  The plan should 
include a brief description of (1) the safety and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped.  Include a brief description of any stopping 
rules for the study, when appropriate.  Depending upon the risk, size and complexity of the 
study, the investigator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibility for this monitoring activity.       
NOTE: Regardless of data and safety monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for protecting the rights, safety, and welfare of subjects 
under his/her care.
The principal investigator will be responsible for reviewing the study data 
after each 5th enrolled patient. The purpose of these reviews will be to 
identify and correct any potentially unsafe practice or result occurring among 
the study population. This includes specifically any delay in uterotonic 
administration, lack of an appropriate uterotonic being administered, or the 
use of a uterotonic in a patient with a contraindication to that drug. 
Any adverse events identified by the principal investigator, or any of the 
other study investigators, will be reported to the PHRC in accordance with 
the PHRC Policy on Unanticipated Problems Involving Risks to Subjects or 
Others, including Adverse Events.
Describe the plan to be followed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safety reports and DSMB reports.  Describe the plan for reporting adverse events to the sponsor 
and the Partners’ IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the Partners’ IRBs.  When the investigator is also the sponsor of the IND/IDE, include 
the plan for reporting of adverse events to the FDA and, when applicable, to investigators at 
other sites.  
NOTE: In addition to the adverse event reporting requirements of the sponsor, the principal 
investigator must follow the Partners Human Research Committee guidelines for Adverse Event 
Reporting
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Upon review at the end of each of 5 patients recruited, the principal 
investigator will note specific frequency of minor and serious adverse events 
experienced by subjects. Any incidence of frequent minor events or any 
single serious adverse event will trigger a report generated for submission to 
the Partners IRB. For any serious concern, the Principal Investigator will halt 
the study until further discussion with the IRB.  
MONITORING AND QUALITY ASSURANCE
Describe the plan to be followed by the principal investigator/study staff to monitor and assure 
the validity and integrity of the data and adherence to the IRB-approved protocol.  Specify who 
will be responsible for monitoring, and the planned frequency of monitoring.  For example, 
specify who will review the accuracy and completeness of case report form entries, source 
documents, and informed consent.  
NOTE: Regardless of monitoring plans by the sponsor or others, the principal investigator is 
ultimately responsible for ensuring that the study is conducted at his/her investigative site in 
accordance with the IRB-approved protocol, and applicable regulations and requirements of the 
IRB.
All physician co-investigators involved in this study will be well informed of 
recruitment procedures, location of study medications storage, appropriate 
handling of medications and timing of administration, as well as other 
protocol details. 
The principal investigator will conduct a review of source documentation 
after every 5 enrolled patients, weekly, or immediately upon recognition of 
any adverse event. The principal investigator will ensure that the study 
protocol is conducted in accordance to the final approved IRB. This includes 
ensuring that recruited patients meet eligibility criteria and are provided with 
study information in advance of enrollment; reviewing consent 
documentation and reviewing collected data to ensure that all items are 
completed, including complications and potential adverse events, and that 
the data is free of patient identifiers; and following-up on any reported 
concerns from patients, study staff, or clinicians.
For guidance, refer to the following Partners policies:
          Data and Safety Monitoring Plans and Quality Assurance
            https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/DSMP_in_Human_Subjects_Research.pdf 
         
          Reporting Unanticipated Problems (including Adverse Events)
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Reporting_Unanticipated_Problems_including_Adverse_Events.pdf
Page 96 of 99

Partners Human Subjects Research Application Form
Filename: Protocol Summary
Version Date:  October 15, 2014
 
14
PRIVACY AND CONFIDENTIALITY
Describe methods used to protect the privacy of subjects and maintain confidentiality of data 
collected.  This typically includes such practices as substituting codes for names and/or medical 
record numbers; removing face sheets or other identifiers from completed 
surveys/questionnaires; proper disposal of printed computer data; limited access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location.  
NOTE: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of sensitive 
data, such as sexual, criminal or illegal behaviors.
All data related to this study will be treated as confidential. Email 
communication to potential subjects at term gestation will be sent securely, 
in accordance with MGB Information Security guidelines. Collected data will 
be consolidated and entered directly in a de-identified fashion into a secure 
electronic capture tool, REDCap. Patient MRNs will be the only patient 
identifier recorded in REDCap; these will be entered with study group 
allocation and study ID number separately from the other study data into a 
secure document on REDCap by the unblinded principal investigator. The 
MRNs will be linked to study information on the randomization sheets, which 
will be viewed only by the unblinded principal investigator and stored in a 
locked filing cabinet in a locked office, accessible only by the principal 
investigator. Any other paper documentation related to study patients and 
containing patient identifiers will be maintained in the same locked filing 
cabinet, accessible only by the principal investigator. 
Only the principal investigator, and one unblinded co-investigator will have 
access to the REDCap files. No one other than the study investigators will 
have any knowledge of the details of the patient’s study information, and 
this data will never be circulated electronically or in any other format.
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE 
PARTNERS
Specimens or data collected by Partners investigators will be sent to research collaborators 
outside Partners, indicate to whom specimens/data will be sent, what information will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects.
No specimens or data will be collected or sent to research collaborators 
outside Partners or participating sites.
Page 97 of 99

Partners Human Subjects Research Application Form
Filename: Protocol Summary
Version Date:  October 15, 2014
 
14
Specifically address whether specimens/data will be stored at collaborating sites outside 
Partners for future use not described in the protocol.  Include whether subjects can withdraw 
their specimens/data, and how they would do so.  When appropriate, submit documentation of 
IRB approval from the recipient institution.
Not applicable to this study.
RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
PARTNERS
When specimens or data collected by research collaborators outside Partners will be sent to 
Partners investigators, indicate from where the specimens/data will be obtained and whether the 
specimens/data will contain identifiers that could be used by Partners investigators to link the 
specimens/data to individual subjects.  When appropriate, submit documentation of IRB 
approval and a copy of the IRB-approved consent form from the institution where the 
specimens/data were collected.
No specimens will be collected from outside Partners or any participating 
sites.
Page 98 of 99

Dear Ms. xxx,
We would like to tell you about an important ongoing study at the Brigham and Women's 
Hospital that you may be eligible for during your delivery. Your obstetrician, Dr. xxx, is 
aware and supportive of this research, and mentioned that you agreed to be contacted 
by the study team. 
The study compares two medications (methylergovonive and carboprost) that are used 
commonly every day to help the uterus contract after birth, but no one knows which one 
is better. This will be the first study to compare them head to head to decide if one is 
more effective than the other. We are attaching a study flier and sample consent form 
here for more information, and we will approach you when you are admitted to Labor & 
Delivery, in case you would like to participate.
If you would like to learn more about the study, please contact the Principal Investigator, 
Dr Jimin Kim at jjkim@bwh.harvard.edu. No action is required on your part otherwise.
Thank you for your consideration and we wish you a safe and happy birth experience!
Sincerely,
The investigators of the Second-Line Uterotonics Study.
Page 99 of 99