Clinical trial NCT02265965
Conditions: Prolonged Second Stage of Labor
Sponsor: University of California, San Francisco
Start date: 2015-10-01; Completion date: 2018-07-01
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Randomized controlled clinical trial of IV nitroglycerin at cesarean delivery for second stage arrest of descent to prevent or uterine extension at the hysterectomy site.

Detailed description:
Intravenous nitroglycerin resulting in uterine relaxation has been standardly utilized for various obstetrics conditions, e.g. breech extraction of second twin in vaginal deliveries, uterine relaxation after tachysystole in labor, prior to external cephalic version, and during difficult fetal extraction during cesarean delivery for arrest of descent in labor. Currently the use of nitroglycerin is at equipoise in obstetrics for difficult cesarean delivery after second stage arrest in labor. The clinical trial will randomize women who undergo cesarean delivery for second stage arrest in labor to receive IV nitroglycerin vs saline at the time of hysterotomy. The primary outcomes will be maternal: uterine extension, blood loss, total fetal extraction time, surgical time; neonatal: cord gases at delivery, apgar scores, admission to neonatal intensive care unit.

Arms: arm 1: Subjects will receive IV nitroglycerin at the time of Hysterotomy. Infusion will be stopped once neonate is delivered arm 2: Subjects will receive IV saline at the time of Hysterotomy. Infusion will be stopped once neonate is delivered
Interventions: intervention 1: intravenous nitroglycerin
Intervention descriptions: intervention 1: Infusion at started at time of hysterotomy and stopped at neonate delivery

Protocol documents:
Prot_SAP_000.pdf: 
Randomized control trial of nitroglycerin during cesarean delivery in the 
second stage of labor 
 
 
NCT02265965 
 
 
Document Date: 10/19/2017 
 
 


Study Application (Version 1.11)
1.0
General Information
*Enter the full title of your study:
Randomized control trial of nitroglycerin during cesarean delivery in the second stage of labor
 
 
*Enter the study number or study alias
RCT of NTG for CD in labor
* This field allows you to enter an abbreviated version of the Study Title to quickly identify this 
study.
 
 
2.0
Add Department(s)
2.1 List the departments associated with this study. The Principal Investigator's department 
should be Primary.:
Primary 
Dept?
Department Name
UCSF - 
 - M_Anesthesia
127037
UCSF - 
 - M_ObGyn-MFM-Core-MFM
123024
 
3.0
List the key study personnel: (Note: external and affiliated collaborators who 
are not in the UCSF directory can be identified later in the Qualifications of 
Key Study Personnel section at the end of the form)
3.1 *Please add a Principal Investigator for the study:
 
Lucero, Jennifer M. MD, MD
Select if applicable
Department Chair
Resident
Fellow
If the Principal Investigator is a Fellow, the name of the Faculty Advisor must be supplied below.
 
3.2 If applicable, please select the Research Staff personnel:
 
A) Additional Investigators
Britton, Atisa B 
 Other Investigator
Farajian, Viken 
 Other Investigator
Henry, Dana E 
 Other Investigator
Lim, Stephanie 
N


 Other Investigator
Page, Shannon M 
 Other Investigator
Thiet-Akram, Mari-Paule 
 Co-Principal Investigator
Yeh, Peter 
 Other Investigator
B) Research Support Staff
Balan, Samantha A 
 Study Recruiter
Gertridge, Lisa C 
 Research Assistant
Leong, Stephanie A 
 Research Assistant
O'Leary, Allison S 
 Research Assistant
Thao, Kao N 
 Research Assistant
Valdez Lopez, Priscila A 
 Research Assistant
Wilson, Lisa 
 Research Assistant
3.3 *Please add a Study Contact:
 
Henry, Dana E 
Lucero, Jennifer M. MD, MD 
The Study Contact(s) will receive all important system notifications along with the Principal 
Investigator. (e.g. The project contact(s) are typically either the Study Coordinator or the Principal 
Investigator themselves).
3.4 If applicable, please add a Faculty Advisor/Mentor:
 
3.5 If applicable, please select the Designated Department Approval(s):
 
Add the name of the individual authorized to approve and sign off on this protocol from your 
Department (e.g. the Department Chair or Dean).
4.0
 Qualifications of Key Study Personnel
4.1  November, 2015 - NEW Definition of Key Study Personnel and CITI Training 
Requirements:    
  
include the Principal Investigator, other investigators and research 
UCSF Key Study Personnel 
personnel who are directly involved in conducting research with study participants or who are directly 
involved in using study participants’ identifiable private information during the course of the 
research. Key Personnel also include faculty mentors/advisors who provide direct oversight to 
        
Postdoctoral Fellows, Residents and Clinical Fellows serving as PI on the IRB application.
 
The 
IRB requires that all Key Study Personnel complete Human Subjects Protection 
Training through CITI prior to approval of a new study, or a modification in 


which KSP are being added. More information on the CITI training requirement 
can be found on our website.
    
   
List the study responsibilities and qualifications of any individuals who qualify as Key Study 
 (KSP) at UCSF and affiliated sites ONLY by clicking the "Add a new row" button. 
Personnel
This 
 
information is required and your application will be considered incomplete without it.
KSP Name
Description of Study 
Responsibilities
Qualifications
Henry, Dana E
Data Collection
Maternal Fetal Medicine Fellow
Thiet-Akram, Mari-Paule
Co-PI
Director of MFM division and 
currently PI in multi center 
RCT drug trial
Dr. Lucero, Jennifer M. MD, MD
PI
Director of Ob-Anesthesia 
research and a translational 
researcher and completed am 
NIH research fellowship
Leong, Stephanie A
Research Recruiter
Recruits for studies on labor 
and delivery with over a year 
of experience
Lim, Stephanie
Data Collection and 
Recruitment
Obstetric Anesthesia Fellow
Gertridge, Lisa C
Research Recruiter
Recruits for studies on labor 
and delivery with over a year 
of experience
O'Leary, Allison S
Research Recruiter
Recruits for studies on labor 
and delivery with over a year 
of experience
Wilson, Lisa
Research Recruiter
Recruits for studies on labor 
and delivery with over a year 
of experience
Britton, Atisa B
Data Collection and 
Recruitment
Obstetric Anesthesia Fellow
Page, Shannon M
Data Collection and 
Recruitment
Obstetric Anesthesia Fellow
Thao, Kao N
Research Recruiter
Recruits for studies on labor 
and delivery with over a year 
of experience
Valdez Lopez, Priscila A
Research Recruiter
Recruits for studies on labor 
and delivery with over a year 
of experience
Farajian, Viken
Data Collection and 
Recruitment
Obstetric Anesthesia Fellow
Yeh, Peter
Data Collection and 
Recruitment
Obstetric Anesthesia Fellow
Balan, Samantha A
Research Recruiter
Recruits for studies on labor 
and delivery with over a year 
of experience


5.0
 Initial Screening Questions - Updated 9/13
(Note: You must answer every question on this page to proceed).
If you are converting to the new form, check questions 5.4, 5.6, 5.7, 5.8 
and 5.10 before saving and continuing to the next section.
5.1  
 Application type:
*
Full Committee 
Expedited 
Exempt 
5.2  
 Risk level 
:
*
(Help Text updated 9/13)
Minimal risk 
Greater than minimal risk 
5.3  
 Subject contact:
*
Yes (including phone, email or web contact) 
No (limited to medical records review, biological specimen analysis, and/or data analysis) 
5.4  
 Funding (past or present):
*
Funded or will be funded (external sponsor, gift, program or specific internal or departmental funds) 
Unfunded (no specific funds earmarked for this project) 
Unfunded student project 
5.5  
The Principal Investigator and/or one or more of the key study personnel has 
 
* 
financial interests
related to this study:
  Yes   
  No
If 
, the Conflict of Interest Advisory Committee (COIAC) office may contact you for additional 
Yes
information.
5.6  
This is an investigator-initiated study:
* 
 Yes   
 No
5.7  
This study 
 involves retrospective records review and/or identifiable biospecimen analysis:
* 
ONLY
  Yes   
  No
5.8  
This is a clinical trial:
* 
 Yes   
 No
Clinical Trial Registration
"NCT" number for this trial:
NCT02265965


5.9  * This is a multicenter study:
  Yes   
  No
5.10  
This application involves the study of 
 or 
 drugs, devices, biologics or in vitro 
* 
unapproved
approved
diagnostics:
 Yes   
 No
5.11  * This application involves a Humanitarian Use Device:
No 
Yes, and it includes a research component 
Yes, and it involves clinical care ONLY 
5.12  
This study involves human stem cells (including iPS cells and adult stem cells), gametes or 
* 
embryos:
No 
Yes, and requires CHR and GESCR review 
Yes, and requires GESCR review, but NOT CHR review 
5.13  * This is a CIRB study (e.g. the NCI CIRB will be the IRB of record):
  Yes   
  No
5.14  
This application includes a request to rely on another IRB (other than NCI CIRB):
* 
  Yes   
  No
Note: If this request is approved, the CHR will 
 review and approve this study. Another institution will 
NOT
be the IRB of record.
6.0
 Funding
6.1  Identify all sponsors and provide the funding details. If funding comes from a Subcontract, please list 
only the Prime Sponsor:        
 
Note: we require only a P Number 
 an A Number for 
OR
funding coming through UCSF. Please avoid these common errors in funding 
       
documentation: 
 
 
DO NOT add the A Number if a P Number was already provided OR update 
the A Number field when a new funding cycle begins. The IRB does NOT 
use this information or want these changes made.   
 add a grant continuation as a new funding source. 
DO NOT
External Sponsor:
View 
Details
Sponsor Name
Sponsor Type
Awardee 
Institution
Contract 
Type:
UCSF RAS 
"P 
number" 
UCSF 
RAS 
System 
Award 
Number 


or 
eProposal 
number 
("A" + 
6 
digits) 
No Sponsor has been added to this IRB Study
Gift, Program, or Internal Funding (check all that apply):
Funded by gift (specify source below)
Funded by UCSF or UC-wide program (specify source below)
Specific departmental funding (specify source below, if applicable)
List the gift, program, or departmental funding source:
Departmental funding through Department RFA
6.2    
   
If you tried to add a sponsor in the question above and it was not in the list, follow these steps:
If funding has already been awarded or the contract is being processed by the Office of 
Sponsored Research (OSR) or Industry Contracts Division (ICD), your sponsor is already in the 
system and the project has an eProposal Proposal or Award number. Check with your 
department's OSR Staff or ICD Officer to ask how the sponsor is listed in the UC sponsor list 
and what the Proposal or Award number is. Click 
 to find your OSR staff and 
 to find 
here
here
your ICD staff.
If your sponsor is not yet in the list, enter it in the box below.
Sponsor not in list 
Only if your sponsor is not yet in the list, type the sponsor's name:
If the funding is administered by the UCSF Office of Sponsored Research, your study will not 
receive CHR approval until the sponsor and funding details have been added to your 
application.
6.3  
This study is currently supported in whole or in part by Federal funding OR has received ANY 
* 
Federal funding in the past 
:
(Help Text updated 9/13)
  Yes   
  No
If 
, indicate which portion of your grant you will be attaching:
yes
The Research Plan, including the Human Subjects Section of your NIH grant or subcontract
For other federal proposals (contracts or grants), the section of the proposal describing human 
subjects work
The section of your progress report if it provides the most current information about your human 
subjects work
The grant is not attached. The study is funded by an award that does not describe specific plans for 
human subjects, such as career development awards (K awards), cooperative agreements, program 
projects, and training grants (T32 awards) OR UCSF (or the affiliate institution) is not the prime 
recipient of the award
7.0
 Sites
7.1  Institutions (check all that apply):
UCSF
China Basin


Helen Diller Family Comprehensive Cancer Center
Mission Bay
Mount Zion
San Francisco General Hospital (SFGH)
SF VA Medical Center (SF VAMC)
Blood Centers of the Pacific (BCP)
Blood Systems Research Institute (BSRI)
Fresno (Community Medical Center)
Gallo
Gladstone
Institute on Aging (IOA)
Jewish Home
SF Dept of Public Health (DPH)
7.2  Check all the other types of sites not affiliated with UCSF with which you are cooperating or 
collaborating on this project 
:
(Help Text updated 9/13)
Other UC Campus
Other institution
Other community-based site
Foreign Country
List the foreign country/ies:
7.3  Check any research programs this study is associated with:
Cancer Center
Center for AIDS Prevention Sciences (CAPS)
Global Health Sciences
Immune Tolerance Network (ITN)
Neurosciences Clinical Research Unit (NCRU)
Osher Center
Positive Health Program
8.0
 Study Design
8.1  
Study design 
:
* 
(Help Text updated 9/13)
This is a study of the effect of IV nitroglycerin on the ease of fetal extraction during cesarean delivery in 
the second stage of labor and thus reducing the incidence of uterine extension.  Nitroglycerin IV is often 
given during cesarean delivery for women who are diagnosed with arrest of descent for uterine relaxation 
and aid in delivery of the fetal head. This is standard obstetric practice, but the use of this medication has 
not been shown to have a significant effect on maternal outcomes in previous studies, and its use has not 
been standardized among obstetric and anesthesia providers. However, in our retrospecitve review of our 
data from our perintatal database in a small subset of women who received nitroglycerin (28/309) there 
was an increase risk of neontal admission to NICU, metabolic acidosis on cord blood gas, and lower apgar 
scores. In an attempt to clarify and standardize the utility and efficacy of this practice, we propose a 
cluster randomized trial of the use of IV nitroglyerin on hysterotomy extension during cesarean delivery 
performed in the second stage of labor. Prior to the start of a new month all cesarean deliveries performed 
in the second stage of labor will undergo randomization to receive nitroglycerin for the entire month vs 
saline for that month. The nitroglycerin or placebo will be administered to the patient at the time of 
hysterotomy prior to fetal extraction. It has become routine in many cases with prolonged second stage to 
administer nitroglycerin during cesarean delivery at the time of fetal head deliver after the obstetrician has 
deemed the delivery difficult, therefore at the time of uterine incision prior to the extraction the obstetric 
anesthesiologist will give a bolus dose of 400mcg nitroglycerin or placebo followed by infusion of 400mcg


/min of nitroglycerin until delivery of the neonate is complete. If during the delivery the obstetrician makes 
an additional request for nitroglycerin the obsetric anesthesiologist will give a 400mcg bolus of known 
nitroglycerin to the patient.
8.2  If this is a clinical trial, check the applicable phase(s) 
:
(Help Text updated 9/13)
Phase I
Phase II
Phase III
Phase IV
9.0
 Scientific Considerations
9.1  Hypothesis 
:
(Help Text updated 9/13)
This study has a hypothesis:
 Yes   
 No
If yes, state the hypothesis or hypotheses:
H1-IV nitroglycerin will decrease uterine incision extensions and blood loss compared to placebo
H2- IV nitroglycerin will decrease overall operative time compared to placebo
H3-IV nitroglycerin will decrease the fetal extraction time (time from hysterotomy to delivery of infant) 
compared to placebo
H4-IV nitroglycerin will have no difference in fetal outcomes compared to placebo
9.2  
List the specific aims:
* 
Aim-1 Uterine relaxation providing ease of delivery of  fetal head would result in reduction of uterine 
extensions and allow for shortened operative times for cesaran delivery. We would like to evaluate the role 
of IV nitroglycerin for improved maternal outcomes in cesearean delivery for arrest of descent.
Aim 1a.To test the hypothesis that use of  IV nitroglycerin during the time of cesarean delivery for 
difficulty delivering fetal head is effective in reducing hysterotomy extensions, blood loss, and improved 
cord blood gases. Measurment of blood loss, if any uterine extensions, and cord blood gas values will be 
analyzed.
Aim 1b. To test the hypothesis that use of  IV nitroglycerin during the time of cesarean delivery for 
difficulty delivering fetal head is effective in reducing total operative time. Monthly IV nitroglycerin 
randomization for cesearen delivery will be performed.  Measurement of total operative time will be 
analyzed.
Aim 1c. To test the hypothesis that use of  IV nitroglycerin during the time of cesarean delivery for 
difficulty delivering fetal head is effective in reducing fetal extraction. Monthly IV nitroglycerin 
randomization for cesearen delivery  will be performed. The obstetrician will be blinded. Measurement of 
time of hysterotomy to delivery of neonate will be analyzed.
 
 
 
9.3  Statistical analysis: 
Sample size- 270 patients per arm based on power calculation of hysterotomy uterine extension alpha = 
0.05, power 0.8
Univariate- We will perform a chi square for the nonparametric outcomes and t-test for the continuous 
outcomes
multiple comparisons performed post-hoc will include bonferroni correction, where applicable.
Mutivariate-We will perform a a logistic regression for the primary and seconary outcomes
 
9.4  If this study has undergone scientific or scholarly review, please indicate which entity performed the 
review:


Cancer Center Protocol Review Committee (PRC) (Full approval is required prior to final CHR approval 
for cancer-related protocols.)
CTSI Clinical Research Center (CRC) advisory committee
Departmental scientific review
Other:
Specify 
:
Other
10.0
 Background
10.1  Background:
The use of nitroglycerin has become routine in breech extraction during twin delivery and recently become 
routinely requested by the obstetricians who are having difficulty delivering a neonate through a 
hysterostomy for both arrest of descent and active phase arrest for cesarean deliveries.  Addtionally it has 
been studied as an alternative and for terbutaline for external cephalic version.  Both IV niroglycerin and 
sublingual nitroglycerin have been used in cases of tachysystole with fetal bradycardia during labor. In 
uterine inversion it is considered the drug of choice prior to induction of volatile anesthetics and is given at 
bolus doses of 1000 mcg IV without any safety concerns. It is a standard medication during open fetal 
surgeries where there is concern of uterine contractions and as such given in bolus IV doses of 200-
400mcg if there is concern of fetal bradycardia secondary to increased uterine tone. The safety profile of 
IV nitorglycerin has been studied and given the broad range of uses in Obstetrics. Recently there is 
thought based on anecdotal evidence that IV nitroglycerin boluses prior to fetal head extraction ease 
delivery of a potential difficult delivery, and has become routinely requested by the obstetrician if there is 
a stuggle to deliver the head during cesarean delivery.  Prior to this becoming adopted based on only 
anecdotal evidence and utilized after time has been lost during a difficult delivery, we propose evaluating 
IV nitroglycerin administration prior to delivery of the neonate and blind obstetricians to the administration 
to better evaluate whether there are benefits of nitroglycerin during fetal head extraction during cesaren 
delivery for arrest of descent.
10.2  Preliminary studies:
Retrospective analysis was performed at UCSF, evaluating the use of nitroglycerin during cesarean delivery 
during the second stage of labor.  nitroglycerin was used in 9% of the total cesarean deliveries and was 
not significantly associated with increased risk of uterine exension. Although the absolute rate of extension 
was lower in the nitroglycerin group a small sample size limited our ability to detect a difference between 
these groups. One finding associated with sublingual nitroglycerin group was the increased rate of NICU 
admissions, metabolic acidosis in cord blood, and lower apgars, however this was not found with 
intravenous nitroglycerin. Given the sample size was small and this was a retrospective review it is unclear 
whether this is a real effect of sublingual nitroglycerin or is sublingual nitroglycerin a surrogate for 
difficulty delivery and prolonged second stage of labor.  
10.3  References:
Alexander et al., Obstet & Gynecol, 2007
David et al., 1997 Obstet & Gynecol
Hilton et al., 2009
Clark et al, 2004 Obstet & Gynecol
If you have a separate bibliography, attach it to the submission with your other study documents. 
11.0
 Sample Size and Eligibility
11.1  Number of subjects that will be enrolled at UCSF and affiliated institutions:


540
11.2  Total number of subjects that will be enrolled at all sites 
:
(Help Text updated 9/13)
540
11.3  Estimated number of people that you will need to consent and screen here (but not necessarily 
enroll) to get the needed subjects:
160/month
11.4  Explain how and why the number of subjects was chosen 
:
(Help Text updated 9/13)
Estimates are based on our perinatal databse calculations for cesarean delivery in the second stage over 
the last 3 years. We conducted a  power calculation to determine amount of subjects needed to see a 
difference in hysterotomy extension during fetal extraction. This sample size was calculated using standard 
alpha of 0.05, this sample size would allow us 80% power to find reduction in hysterotomy extension from 
baseline risk of 25% to 15% with treatment.  This was chosen as it is considered a clinically significant 
difference in this outcome.  
 
11.5  * Eligible age range(s):
0-6 years
7-12 years
13-17 years
18+ years
11.6  Inclusion criteria:
We plan to include all women with a term (>/= 37weeks) gestation, undergoing cesarean delivery in the 
second stage of labor.  This would also include those who underwent a failed assisted vaginal delivery with 
forceps or vaccuum and need to undergo cesarean delivery.
11.7  Exclusion criteria:
Women who delivery vaginally either via operative vaginal delivery or spontaneous vaginal delivery
Any cesarean delivery under general anesthesia
Primary or repeat cesarean delivery electively perfomred or in the first stage of labor
 
11.8  There are inclusion or exclusion criteria based on gender, race or ethnicity:
 Yes   
 No
If
, please explain the nature and rationale for the restrictions:
 yes
This is a study that requires women who are pregnant underoing cesarean delivery, therefore their gender 
needs to be female.
12.0
 Drugs and Devices
12.1  
Investigational drugs or biologics will be used 
approved drugs or biologics will be studied 
* 
OR 
under this application:
 Yes   
 No


12.2  
edical devices or in vitro diagnostics will be used 
 approved medical devices or 
* Investigational m
OR
in vitro diagnostics will be studied under this application:
  Yes   
  No
12.3  
A Non-Significant Risk (NSR) determination is being requested for an investigational device:
* 
  Yes   
  No
12.4  
  If the sponsor’s protocol does not list the IND/IDE number, you 
Verification of IND/IDE numbers:
must submit documentation from the sponsor or FDA identifying the IND/IDE number for this study. 
Attach this documentation in the Other Study Documents section of the Initial Review Submission 
Packet.
13.0
 Study Drug Details
13.1  List the drugs or biologics that will be studied:
View 
Details
Drug Name
FDA Approved
A new drug or a 
new use of 
approved drug:
IND Number
Trade Drug 
Name: NITROGLYCERIN
Generic Drug 
Name: NITROGLYCERIN
Investigational 
Drug Name:
Yes 
No 
 
Trade Drug Name:
NITROGLYCERIN 
Generic Drug Name:
NITROGLYCERIN 
Investigational Drug Name:
 
Identify the name of the 
manufacturer or source of 
investigational drug/biologic:
American Regent, inc  
Is the drug supplied at no cost?
Yes  
Is the Drug FDA Approved:
Yes  
Is this a new drug or a new use of 
an already approved drug
No  
Is an IND necessary
No  
IND Number
 
Who holds the IND:
N/A  
IND details:
 
If FDA Approved and an IND is 
not required, Please provide a 
rationale for exemption:
The drug is currently used for this obstetrical clinical scenario and 
has been for over 20 years.  
Are you currently using this IND 
in another research project?
No  
If yes, list the IRB Number(s):
 
Will the investigational pharmacy 
be dispensing?
No  


If the source is not a FDA licensed 
facility, provide details regarding 
the purity, quality, stability and 
sterility of the investigational drug
/biologic:
 
14.0
 Other Approvals and Registrations
14.1  
 
Do any study activities take place on patient care units:
* 
 Yes   
 No
If 
, attach a letter of support for the study from the involved patient care manager(s).
Yes
14.2  
Does your protocol involve any radiation exposure to patients/subjects? The UCSF Radiation 
* 
 
Safety Committee requires review of your protocol if it includes administration of radiation as part of 
standard of care 
 research exposures:
OR
  Yes   
  No
14.3  
This study may generate genetic data that may be broadly shared (e.g. submitted to NIH for 
* 
 in 
, 
, etc):
Genome-Wide Association Studies (GWAS)
dbGaP TCGA
  Yes   
  No
14.4  
This study involves administration of vaccines produced using recombinant DNA technologies to 
* 
human subjects:
  Yes   
  No
14.5  
This study involves human gene transfer (NOTE: Requires NIH Recombinant DNA Advisory 
* 
Committee (RAC) review prior to CHR approval):
  Yes   
  No
14.6  This study involves other regulated materials and requires approval and/or authorization from the 
following regulatory committees:
Institutional Biological Safety Committee (IBC)
Specify BUA #:
Institutional Animal Care and Use Committee (IACUC)
Specify IACUC #:
Radiation Safety Committee
Specify RUA #:
Radioactive Drug Research Committee (RDRC)
Specify RDRC #:


Controlled Substances
15.0
 Procedures
15.1  
Procedures/Methods 
* 
(Help Text updated 9/13)   For clinical research list all study procedures, test 
and treatments required for this study, including when and how often they will be performed. If 
there are no clinical procedures, describe the Methods:
At the time of cesarean delivery, all consented patients that meet the inclusion criteria subjects 
undergoing cesarean delivery in the second stage will be moved to the operating room for cesarean 
delivery.  The anesthesia providers will have the study drug on an infusion pump, based on monthly 
randomization. Standard procedures for cesarean delivery will be undertaken. Standard procedure for 
cesarean delivery in the second stage with an epidural in place include bolusing local anesthetic for 
anesthesia effect, typically the drug utilized in 2% lidocaine in amounts of 15-20 ml to achieve an 
anesthetic block to T4 dermatome level.  This level of anesthesia typically produces hypotension in the 
patient and the standard practice is to start an infusion of phenylephrine in typical infusions of 25-50mcg
/min  titrated to acheive the patient's normal blood pressure level prior to labor. This is typicall done 
whether patient receives IV NTG or not.  At the announcement of uterine incision by the obstetrical team, 
the anesthesia provider will bolus through the infusion pump 2ml (400 mcg NTG or saline) of study drug 
and will start the infusion at 800mcg/min immediately following the bolus dose.  An equal amount ml of 
saline will be given for the placebo group.  The infusion of the study drug will be discontinued after 
delivery of the infant or when 1600mcg total NTG is reached. In addition, when we give NTG the 
anesthesia provider will give IV phenylephrine (a standard vasopressor) to prevent any potential 
hypotension at the dose of 100mcg for every 400mcg of IV NTG. The anesthesia provider will not give the 
phenylephrine dose if the study patient has blood pressure above their baseline and will not give the bolus 
of phenylephrine if the study patient is receiving saline (control) drug. The patient will otherwise be 
treated under the standard care for cesarean delivery which includes can include the use of phenyleprhine 
infusion titrated to patients normal blood pressure prior to the induction of local anesthesia for cesarean 
delivery. This study was designed specifically such that the anesthesia provider will not be blinded to the 
drug.
If the neonatal extraction is difficult and the attending obstetrician attempts delivery and is unable to 
deliver the neonate, he or she may request that the anesthesia provider give known IV NTG at 400mcg 
bolus and continue the infusion at 800mcg/min until delivery of the neonate.  However, this will only be 
given if they previously received saline.  If the patient has already received NTG the team will be told that 
NTG has been given and continue the infusion until the maximum dose of 1600mcg has been given.
If you have a procedure table, attach it to the submission with your other study documents.
15.2  Interviews, questionnaires, and/or surveys will be administered or focus groups will be conducted:
  Yes   
  No
List any standard instruments used for this study:  
Attach any non-standard instruments at the end of the application.
15.3  Conduct of study procedures or tests off-site by non-UCSF personnel:
  Yes   
  No
If yes, explain:
15.4  Sharing of experimental research test results with subjects or their care providers:


  Yes   
  No
If yes, explain:
15.5  
Specimen collection for future research and/or specimen repository/bank administration:
* 
  Yes   
  No
15.6  Time commitment (per visit and in total):
None
15.7  Locations:
Labor and Delivery
15.8  Describe the resources in place to conduct this study in a way that assures protection of the rights 
and welfare of participants:
All outcome information is currently being collected in a secured/maintained in a perinatal database.
16.0
 Alternatives
16.1  Study drug or treatment is available off-study:
Yes 
No  
Not applicable 
16.2  
Is there a standard of care (SOC) or usual care that would be offered to prospective subjects at 
* 
UCSF (or the study site) if they did not participate:
 Yes   
 No
If yes, describe the SOC or usual care that patients would receive if they choose not to participate:
Patients who choose not to participate in the study will undergo cesarean delivery according to the 
institutional standard.  The provider may choose to use nitroglycerin during the surgery based upon his
/her clinical judgement. If the patient does not agree to enrol in the study the obstetrics provider will 
attempt to delivery the neonate and if they have trouble with the neonatal extraction they can request 
nitroglycerin which is the current standard.  They will be given the standard does which is 400mcg bolus of 
IV nitroglycerin followed by a 800mcg/min infusion until maximum dose of 1600mcg total of nitroglycerin 
is given.
16.3  Describe other alternatives to study participation that are available to prospective subjects:
If the patient choses to not enroll in the study the obstetrics provider will attempt to delivery the neonate 
and if they have trouble with the neonatal extraction from the uterus they can request IV nitroglycerin 
which is the current standard.  They will be given the standard dose which, is 400mcg bolus of IV 
nitroglycerin followed by a 800mcg/min infusion until the neonate is delivered or the maximum dose of 
1600mcg total of nitroglycerin is given.
17.0
 Risks and Benefits
17.1  
Risks and discomforts:
* 


Nitroglycerin is currently being used at the obstetrician's request after prolonged struggle to 
deliver neonatal head. Nitroglycerin half life is 2.3 minutes.  There is no evidence of embryotoxic 
or tetatogenic effects, although those would be of limited significance given administration in 
labor.  It is typically tolerated well as it is short-acting; the most common side effects are headache and 
hypotension in volunteer (non-obstetric) patients.
Phenyleprhine insfusion is a standard vasopressor used in obstetrics for hypotension during induction of 
local anesthestic anesthesia for neuraxial technique it is standardly started with the local anesthetic 
bolus.  Risk fo phenyeprhine infusion is hypertention and bradycardia, however, the dose it titrated by 
anesthesia provider to maintain patents pre labor blood pressure.  Phenyleprhine has been widely studied 
in obstetrics literature and compared to ephedrine which was previoulsy thought to be the drug of choice, 
however extensive RCT studies have shown phenyleprhine to be a superior drug as it has 
favorable fetal metabolism and improved umbilical blood gases compared to ephedrine. Ref: Lee A, 
Ngan Kee WD, Gin T. A quantitative, systematic review of randomized controlled trials of ephedrine versus phenylephrine 
for the management of hypotension during spinal anesthesia for cesarean delivery. Anesth Analg 2002; 94: 920–6.
review of randomized controlled trials of ephedrine versus
 
 
 
 
 
 
 
phenylephrine for the management of hypotension during
 
 
 
 
 
 
spinal anesthesia for cesarean delivery. Anesth Analg 2002;
 
 
 
 
 
 
 
94: 920–6.
 
Currently this is being utilized as a standard by many obstetricians after they struggle with 
neonatal head extraction.  In our limited retrospective review of data at our institution we have 
found in the patients who received sublingual (SL) nitroglycerin after the obstetrcians had 
struggled fetal extraction delivery there were increased rates of NICU admission, metabolic 
acidosis in cord bloods, and lower apgar scores, but not for IV- nitroglycerin. In this same 
retrospective review we have found that there was no difference in maternal outcomes, fetal 
extraction time, blood loss, need for tranfusion compared to control for either nitroglcerin group 
(IV or SL).  It is unclear in this retrospective review whether this is due to intrinsic effects of 
sublingual nitroglycerin or secondary to other factors, e.g. prolonged pushing in the second stage, 
difficult fetal extraction, etc.  Given that this medication is utilized in many clinical scenarios in 
obstetrics and for this particular clinical scenario a randomized control trial is warranted to 
evaluate any benefits or risks of nitroglycerin in cesarean delivery for second stage arrest.
In a retrospective review of patients at our institution who received nitroglycerin compared to a 
cohort who did not recieve nitroglycerin there was no difference in mean arterial blood pressure 
between groups and some patients in both group (nitoglycerin and no nitroglycerin) received 
phenyephrine.
17.2  Steps taken to minimize risks to subjects:
all information will be stored on a secured maintained database already in existence.
17.3  Benefits to subjects:
 
 Yes   
 No
If yes, describe:
Potential reduction in uterine hysterotomy extension, which may impact long term maternal/neonatal 
outcomes.  Given that this medication is utilized in many clinical scenarios in obstetrics and for this 
particular clinical scenario a randomized control trial is warranted to evaluate any benefits nitroglycerin in 
cesarean delivery for second stage arrest.
17.4  Benefits to society:
Potential improved understanding of obstetric options/care women in this clinical scenario and better 
understand whether this currenlty standardly utilized treatment poses any neonatal risks.
17.5  Explain why the risks to subjects are reasonable: 
This is a widely used drug in obstetrics and has been used for this exact clinical scenario for years and has 
not shown any maternal risks.  A randomized  controlled clinical trial of nitroglycerin in this clinical 
scenario at this point is necessary to evaluate any potential negative neotnatal effects and to ellucidate 
whether there are any potential benefits to a standard route, timing, and dose of nitroglycerin.


18.0
 Data and Safety Monitoring Plan
18.1  Describe the plan for monitoring data and safety 
:
(Help Text updated 9/13)
We will have a data and safety monitoring group comprised of an Ob-anesthesia and Maternal Fetal 
Medicine specialist  who will review the data and discuss any adverse effects every 6 months during the 
trial.
18.2  This study requires a Data and Safety Monitoring Board:
Yes 
No or not sure 
If 
, press 
 to move to the next section of the application.
yes
SAVE and CONTINUE
18.3  If 
, provide rationale:
No
Social/Behavioral research 
Phase I trial 
Treatment IND/Compassionate Use Trial 
Other (explain below) 
If 
 explain:
Other,
.
19.0
 Data and Safety Monitoring Board
19.1  Provide details from the Data and Safety Monitoring Board's charter, including meeting frequency, 
and affiliations and qualifications of members:
Obstetric Anesthesiologist Dr. Mark Rosen Professor Emeritus and Maternal Fetal Medicine specialist, Dr. 
Mary Norton who will meet every 6 months  
 
Dr. Rosen has had significant clinical experience in Obstetric Anesthesia and the use of both intravenous 
and sublingual nitroglyerin thoughout his career. Dr. Mary Norton is a leader in Maternal Fetal Medicine 
and has implementated several clinical trials both at UCSF through the UC consortium and at Stanford .
These individuals are not part of the study personnel and have significant experience in clinical research.
 
19.2  All of the members of the Data and Safety Monitoring  Board are independent of the sponsor:
 Yes   
 No
20.0
 Confidentiality and Privacy
20.1  Plans for maintaining privacy in the research setting:
all patient information is part of the secure and maintaned perinatal database
20.2  Possible consequences to subjects resulting from a loss of privacy:
loss of patient confidentiality


20.3  Study data are:
Derived from the Integrated Data Repository (IDR) or The Health Record Data Service (THREDS) at 
SFGH
Derived from a medical record (e.g. APeX, OnCore, etc. Identify source below)
Added to the hospital or clinical medical record
Created or collected as part of health care
Used to make health care decisions
Obtained from the subject, including interviews, questionnaires
Obtained from a foreign country or countries only
Obtained from records open to the public
Obtained from existing research records
None of the above
If 
, identify source:
derived from a medical record
20.4  Identifiers may be included in research records:
 Yes   
 No
If 
, check all the identifiers that may be included:
yes
Names
Dates
Postal addresses
Phone numbers
Fax numbers
Email addresses
Social Security Numbers*
Medical record numbers
Health plan numbers
Account numbers
License or certificate numbers
Vehicle ID numbers
Device identifiers or serial numbers
Web URLs
IP address numbers
Biometric identifiers
Facial photos or other identifiable images
Any other unique identifier
* Required for studies conducted at the VAMC
20.5  Identifiable information might be disclosed as part of study activities:
  Yes   
  No
If 
, indicate to whom identifiable information may be disclosed:
yes
The subject's medical record
The study sponsor
Collaborators
The US Food & Drug Administration (FDA)
Others (specify below)


A Foreign Country or Countries (specify below)
If 
, specify:
Others
20.6  Indicate how data are kept secure and protected from improper use and disclosure (check all that 
apply):   NOTE: Whenever possible, do not store subject identifiers on laptops, PDAs, or other 
portable devices. If you collect subject identifiers on portable devices, you MUST encrypt the devices.
Data are stored securely in My Research
Data are coded; data key is destroyed at end of study
Data are coded; data key is kept separately and securely
Data are kept in a locked file cabinet
Data are kept in a locked office or suite
Electronic data are protected with a password
Data are stored on a secure network
Data are collected/stored using REDCap or REDCap Survey
Data are securely stored in OnCore
20.7  Additional measures to assure confidentiality and protect identifiers from improper use and 
disclosure, if any:
20.8  This study may collect information that State or Federal law requires to be reported to other officials 
or ethically requires action:
  Yes   
  No
Explain:
20.9  This study will be issued a Certificate of Confidentiality:
  Yes   
  No
21.0
 Subjects
21.1  Check all types of subjects that may be enrolled:
Inpatients
Outpatients
Healthy volunteers
Staff of UCSF or affiliated institutions
21.2  Additional vulnerable populations:
Children
Subjects unable to consent for themselves
Subjects unable to consent for themselves (emergency setting)
Subjects with diminished capacity to consent
Subjects unable to read, speak or understand English
Pregnant women
Fetuses


Neonates
Prisoners
Economically or educationally disadvantaged persons
Investigators’ staff
Students
Explain why it is appropriate to include the types of subjects checked above in this particular study:
This is evaluating our routine use of nitroglycerin for cesarean delivery and requires pregnant women for 
cesarean delivery
Describe the additional safeguards that have been included in the study to protect the rights and welfare 
of these subjects and minimize coercion or undue influence:
Those subjects included in the study will will undergo the usual standard of care on the obstetric 
suite.  The data collected is already part of the perinatal database that is secure.
22.0
 Inclusion of Children in Research
22.1  This study will enroll children who can legally consent for themselves:
  Yes   
  No
If 
 explain why they can consent for themselves in the research setting:
yes,
If you will 
 be enrolling children who can legally consent for themselves, press 
ONLY
SAVE and 
 to skip the rest of this section.
CONTINUE
22.2  Select all the regulatory categories that apply:
No greater than minimal risk (45 CFR 46.404, 21 CFR 50.51)
Greater than minimal risk but presenting prospect of direct benefit (45 CFR 46.405, 21 CFR 50.52)
Greater than minimal risk (though only a minor increase over minimal risk) and no prospect of direct 
benefit but likely to yield generalizable knowledge about the subjects disorder or condition (45 CFR 
46.406, 21 CFR 50.53)
Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate 
a serious problem affecting the health or welfare of children (45 CFR 46.407, 21 CFR 50.54)
Explain why the research in this study falls under the above category or categories:
22.3  Parental permission or waiver:
Parental permission will be obtained
Waiver of parental permission is requested: Parental permission is not a reasonable requirement
Waiver of parental permission is requested: The waiver meets the provisions for a waiver of consent 
set forth in 45 CFR 46.116, Subpart A
If you are requesting a 
, explain why the study meets the regulatory 
waiver of parental permission
criteria for this waiver:
22.4  Assent of children or waiver:
Assent of children old enough to provide assent will be obtained
Waiver of assent is requested: Children cannot be consulted or the research has prospect of direct 


benefit only available in the study
Waiver of assent is requested: The waiver meets the provisions for a waiver of consent set forth in 45 
CFR 46.116, Subpart A
If you are requesting a 
, explain why the study meets the regulatory criteria for 
waiver of child's assent
this waiver:
Neonates are involved in the study and will not be able to assent.
 
22.5  Documentation of permission and assent (select all that will be used):
Permission form addressed to the parents
Simplified assent form addressed to the child, 7-12 years old (parents get separate form)
Assent form addressed to the child, 13 years and older (for subjects and parents)
Assent form addressed to the child, 13 years and older (parents get separate form)
Check one:
One parent's signature will be obtained 
Two parents' signatures will be obtained 
If this study is approvable under .404 or .405 and you plan to get permission from only one parent, 
explain why you think one parent's permission is sufficient:
The data collected is currenlty collected in a secure form as part of the perinatal database and is related to 
the obstetrical record and is the following: APGAR scores, umbilical cord blood gases, and admission to the 
NICU.  These are currenlty found in the obstetrical record and startdardly collected as part of the perinatal 
database.  No additional information will be collected from tne neonate or the neonatal record.  We will not 
need access to the neontal record.
22.6  This study may enroll wards of the state:
  Yes   
  No
23.0
 Inclusion of Pregnant Women, Fetuses, and/or Neonates
23.1  Review the regulatory categories by clicking on the Help bubble and identify all sections of 45 CFR 
46 Subpart B under which you believe the research falls and provide study-specific information 
showing why the research falls within those sections:
Pregnant women as this group will be the only subject group undergoing cesarean delivery
24.0
 Recruitment
24.1  
 Methods (check all that apply):
*
Study investigators (and/or affiliated nurses or staff) recruit their own patients directly in person or by 
phone.
Study investigators recruit their own patients by letter. Attach the letter for review.
Study investigators send a “Dear Doctor” letter to colleagues asking for referrals of eligible patients. If 
interested, the patient will contact the PI or the PI may directly recruit the patients (with documented 
permission from the patient). Investigators may give the referring physicians a study information 
sheet for the patients.
Study investigators provide their colleagues with a “Dear Patient” letter describing the study. This 
letter can be signed by the treating physicians and would inform the patients how to contact the study 
investigators. The study investigators may not have access to patient names and addresses for mailing


Advertisements, notices, and/or media used to recruit subjects. Interested subjects initiate contact 
with study investigators. Attach ads, notices, or media text for review. In section below, please explain 
where ads will be posted.
Study investigators identify prospective subjects through chart review. (Study investigators request a 
Waiver of Authorization for recruitment purposes.)
Large-scale epidemiological studies and/or population-based studies: Prospective subjects are 
identified through a registry or medical records and contacted by someone other than their personal 
physician. (Study investigators request a Waiver of Authorization for recruitment purposes.)
Direct contact of potential subjects who have previously given consent to be contacted for participation 
in research. Clinic or program develops a CHR-approved recruitment protocol that asks patients if they 
agree to be contacted for research (a recruitment database) or consent for future contact was 
documented using the consent form for another CHR-approved study.
Study investigators list the study on the School of Medicine list of UCSF Clinical Trials website or a 
similarly managed site. Interested subjects initiate contact with investigators.
Study investigators recruit potential subjects who are unknown to them through methods such as 
snowball sampling, direct approach, use of social networks, and random digit dialing.
Other
If 
, explain:
Other
24.2  
How, when, and by whom eligibility will be determined:
* 
Recruiters will review the charts of patients who are coming into the prenatal clinics at UCSF. The charts 
will be viewed on APeX and patients who meet eligibility criteria will be approached in the waiting area 
before their visit and given the opt-in form to review. We have found this approach method to be very 
successful in multiple studies during pregnancy and prenatal care. Recruitment will not interrupt usual 
clinic flow and patient care. In addition to outpatient recruitment, pregnant women who are admitted to 
labor and delivery are seen by anesthesia for a analgesic consultation who have not been already been 
evaluated during our outpatient recruitment will be approached. The study team will only approach women 
who are not in labor and will discuss the study and obtain consent.  Of those patient's that consent for the 
study only 5-10% will be eligible fo the study. Eligbility for the study requires the subject to need a 
cesarean delivery in the second stage of labor.  As such many women may consent for the study, but not 
become eligible as they will deliver vaginally.
24.3  
How, when, where and by whom potential subjects will be approached:
* 
Recruitment will occur either of the following ways:
1-Recruiters will review the charts of patients who are coming into the prenatal clinics at UCSF. The 
charts will be viewed on APeX and patients who meet eligibility criteria will be approached in the waiting 
area before their visit. We have found this approach method to be very successful in multiple studies 
during pregnancy and prenatal care. Recruitment will not interrupt usual clinic flow and patient care.
2-The study team will approach after anesthesia consultation is completed and the potential candidate is 
deemed not in active labor.
24.4  * Protected health information (PHI) will be accessed prior to obtaining consent:
 Yes   
 No
25.0
 Waiver of Consent/Authorization for Recruitment 
Purposes
This section is required when study investigators (and/or affiliated 
nurses or staff) recruit their own patients directly.
25.1  
Study personnel need to access protected health information (PHI) during the recruitment process 
* 
and it is not practicable to obtain informed consent until potential subjects have been identified:


Yes 
If 
, a waiver of consent/authorization is NOT needed.
no
25.2  
 A waiver for screening of health records to identify potential subjects poses no more than minimal 
* 
risk to privacy for participants:
Yes 
If 
, a waiver of authorization can NOT be granted.
no
25.3  
Screening health records prior to obtaining consent will not adversely affect subjects' rights and 
* 
welfare:
Yes 
If 
, a waiver of authorization can NOT be granted.
no
25.4  
Check all the identifiers that will be collected prior to obtaining informed consent:
* 
Names
Dates
Postal addresses
Phone numbers
Fax numbers
Email addresses
Social Security Numbers*
Medical record numbers
Health plan numbers
Account numbers
License or certificate numbers
Vehicle ID numbers
Device identifiers or serial numbers
Web URLs
IP address numbers
Biometric identifiers
Facial photos or other identifiable images
Any other unique identifier
None
Note: HIPAA rules require that you collect the minimum necessary.
25.5  
 Describe any health information that will be collected prior to obtaining informed consent:
*
Review of gestational age and reason for admission will be reviewed prior to obtaining consent, but will not 
be stored once reviewed
Note: HIPAA requires that you collect the minimum necessary.
25.6  
Describe your plan to destroy the identifiers at the earliest opportunity consistent with the 
* 
research 
 provide a health or research justification for retaining the identifiers, or indicate and 
or
explain that retention is required by law:


The patient information is stored on a secure/maintained perinatal database.  Randomization will be 
performed based on month and once enrollment is complete the patient names and MRN will be destroyed.
26.0
 Informed Consent
26.1  * Methods (check all that apply):
Signed consent will be obtained from subjects and/or parents (if subjects are minors)
Verbal consent will be obtained from subjects using an information sheet or script
Electronic consent will be obtained from subjects via the web or email
Implied consent will be obtained via mail, the web or email
Signed consent will be obtained from surrogates
Emergency waiver of consent is being requested for subjects unable to provide consent
Informed consent will not be obtained
26.2  
Process for obtaining informed consent:
* 
Patient will be approached at admission to labor and delivery.
26.3  
How investigators will make sure subjects understand the information provided to them:
* 
Confirm understanding by having the potential subject repeat back the general study plan and answer any 
additonal questions the potential subject may have.
27.0
 Financial Considerations
27.1  Subjects payment or compensation method (check all that apply):
Payments will be (check all that apply):
Subjects will not be paid
Cash
Check
Debit card
Gift card
Reimbursement for parking and other expenses
Other:
Specify 
:
Other
27.2  Describe the schedule and amounts of payments, including the total subjects can receive for 
completing the study. If deviating from recommendations in Subject Payment Guidelines, include 
specific justification below. 
no payments as this is part of standard of care
27.3  Costs to Subjects:  Will subjects or their insurance be charged for any study procedures?
  Yes   
  No
If 
 describe those costs below, and compare subjects’ costs to the costs associated with alternative 
yes,
care off-study. Finally, explain why it is appropriate to charge those costs to the subjects.


28.0
 CTSI Screening Questions
28.1  
This study will be carried out at one of the UCSF Clinical Research Services (CRS) centers or will 
* 
utilize CRS services. CRS centers are at the following sites:
SFGH Clinical Research Center
Moffitt Adult Clinical Research Center
Moffitt Hospital Pediatrics & NCRC
Mount Zion Hospital Clinical Research Center
Tenderloin Center
CHORI Children's Hospital Pediatrics & Adult Clinical Research Center
Kaiser Oakland Research Unit
SF VA Medical Center Clinical Research Unit
  Please note: Effective 3/1/14, the CRS form will no longer be completed and submitted in iRIS. The 
CRS budget request form can be found at: https://accelerate.ucsf.edu/files/crs
 
/BudgetRequest2015.docx. Follow the instructions on the form to submit.  Even if you click 'Yes' to 
this question, the form will no longer proceed to the Clinical Research Services (CRS) Application 
Form section.
  Yes   
  No
28.2  This project involves community-based research:
  Yes   
  No
28.3  This project involves practice-based research:
  Yes   
  No
29.0
 End of Study Application
29.1  End of Study Application Form   To continue working on the Study 
: Click on the section you need to edit in the left-hand menu. Remember to save 
Application
  
through the entire Study Application after making changes.  If you are done working on the 
: Click Save and Continue. If this is a new study, you will automatically 
Study Application
enter the Initial Review Submission Packet form, where you can attach consent forms or 
other study documents. Review the 
 for a list of required 
Initial Review Submission Checklist
 
attachments.   Answer all questions and attach all required documents to speed up your 
 
approval.