Clinical trial NCT02806024
Conditions: Placenta Accreta Postpartum Hemorrhage Cesarean Section Tranexamic Acid
Sponsor: University of California, San Francisco
Start date: 2016-11-01; Completion date: 2018-08-01
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this pilot study is to determine if intravenous tranexamic acid (TXA) is effective for reducing blood loss during high risk surgical procedures related to placenta previa and placenta accreta. TXA is currently used in other types of surgery for patients who are expected to have a large blood loss, such as orthopedic or open heart surgery.

Detailed description:
To date, no novel or pharmacologic methods of reducing blood loss have been described for women at risk for placenta accreta. Intravenous tranexamic acid (TXA), a drug with anti-fibrinolytic activity, is routinely used in elective orthopedic and cardiac surgery to reduce blood loss. Intravenous tranexamic acid is currently FDA approved for use in patients undergoing cardiac surgery or total knee arthroplasty or total hip arthroplasty to reduce peri- and post-operative blood loss and to reduce the need for blood transfusion. There has been growing interest in the application of tranexamic acid in obstetrics and gynecology. In multiple international studies, intravenous TXA has been shown to significantly reduce blood loss when given prophylactically with cesarean delivery or vaginal delivery without an increase in morbidity from adverse thrombotic events. TXA has not been studied in the particular population of patients requiring cesarean hysterectomy for placenta previa or accreta. This inexpensive, low risk medication has potential to greatly reduce perioperative morbidity and cost when used in a high risk obstetrical population.

Arms: arm 1: Patients will be randomized to treatment or placebo arms preoperatively. In our treatment arm of pregnant patients with suspected placenta accreta or at high risk for placenta accreta, patients will receive 1 gram intravenous TXA administered over 10 minutes immediately after delivery of the infant. The drug will be prepared and ready to hang at the beginning of the case. The study drug will be administered only once. arm 2: Patients will be randomized to treatment or placebo arms preoperatively. In our placebo arm of pregnant patients with suspected placenta accreta, patients will receive plain normal saline in a 50 cc bag identical to the preparation of study drug immediately after delivery of the infant.
Interventions: intervention 1: Tranexamic Acid intervention 2: Placebo Drug
Intervention descriptions: intervention 1: None intervention 2: 50 cc Normal Saline IV

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
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Document date: 6/4/2016 
    
NCT02806024 
 
ID: 2016036     Perioperative Administration of Tranexamic Acid for Placenta 
Previa and Accreta Study 
 
Perioperative Administration of Tranexamic Acid for Placenta Previa and Accreta Study 
(TAPPAS): A Randomized, Placebo-controlled Double Blind Trial 
UCSF Fresno Department of Obstetrics and Gynecology   
 
Brief Synopsis 
The purpose of this pilot study is to determine if intravenous tranexamic acid (TXA) is effective for 
reducing blood loss during high risk surgical procedures related to placenta previa and placenta 
accreta. TXA is currently used in other types of surgery for patients who are expected to have a 
large blood loss, such as orthopedic or cardiac surgery.  The drug will be given AFTER delivery of 
the baby, so there is no risk of harm to the infant when participating in the study. 
Background  
Significance: The incidence of morbidly adherent placenta is rising due to increasing cesarean 
rates, and is currently estimated at 1 in 500 to 700 deliveries. Placenta accreta, a condition in 
which the placenta abnormally invades the uterine wall, carries a high risk of operative 
complications and often requires cesarean hysterectomy. Cesarean hysterectomy leads to higher 
intraoperative blood loss and morbidity when compared to a routine cesarean delivery. 
Retrospective reviews estimate there a 40% risk of requiring blood transfusion over ten units, and 
a 7% risk of maternal death (1).  
Placenta accreta can be suspected antenatally based on certain risk factors, such as prior 
cesarean delivery and abnormal placenta location. For example, a woman with 3-4 prior cesarean 
deliveries and a placenta previa (low lying placenta) has a 60% risk of placenta accreta (14). 
Additional ultrasound and/or MRI studies can identify suspicious imaging features. However, 
diagnosis cannot be confirmed until the time of surgery, at which point abnormal placental 
behavior (hemorrhage, or failure of the placenta to detach) may be observed. The diagnosis is 
confirmed by final pathology report. Women with multiple prior cesarean sections, placenta 
previa, and placenta accreta have greater expected intraoperative blood loss, perioperative 
complications and morbidity than primary (first-time) cesarean sections (14). 
Placenta accreta is as challenging to treat as it is to diagnose. The only commonly described 
innovation thus far is interventional radiology preoperative placement of balloon catheters in the 
uterine arteries to reduce intraoperative bleeding. Yet the evidence supporting this practice is 
mixed and in some series has not been shown to provide a statistically significant reduction in 
blood loss (2). Additionally, some motivated patients with accreta who wish to preserve the uterus 
do not undergo hysterectomy, and instead are given methotrexate after delivery to encourage 
absorption of the placenta. This approach frequently results in failure and hysterectomy at a later 
date. Current recommendations include referral of patients with a high suspicion of accreta to a 
tertiary care center for delivery, preparedness for a massive transfusion protocol if needed, and a 
planned, late preterm delivery to occur with coordinated support of surgical subspecialists (such 
as oncology backup) if bladder or other visceral organ involvement is suspected.  
Innovation: To date, no novel or pharmacologic methods of reducing blood loss have been 
described for women at risk for placenta accreta. Intravenous tranexamic acid (TXA), a drug with 


 
 
 
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anti-fibrinolytic activity, is routinely used in elective orthopedic and cardiac surgery to reduce 
blood loss. Intravenous tranexamic acid is currently FDA approved for use in patients undergoing 
cardiac surgery or total knee arthroplasty or total hip arthroplasty to reduce peri- and post-
operative blood loss and to reduce the need for blood transfusion. Although off label, the use of 
TXA in trauma patients with massive blood loss is also well described (3,4). The FDA states that 
prospective studies investigating the optimal use of tranexamic acid in trauma and other settings 
are needed and encouraged (5). 
There has been growing interest in the application of tranexamic acid in obstetrics and 
gynecology. In multiple international studies, intravenous TXA has been shown to significantly 
reduce blood loss when given prophylactically with cesarean delivery or vaginal delivery without 
an increase in morbidity from adverse thrombotic events (6-9). Currently, a large, international 
(n=15,000) clinical trial is being conducted in middle- and low-income countries investigating the 
use of TXA for post-partum hemorrhage after vaginal delivery (10). A recent Danish study has 
also been completed regarding the use of TXA in benign gynecologic surgeries, i.e. routine 
hysterectomy (11). Furthermore, in March of 2016, Pacheco et al released new guidelines 
recommending the use of TXA in all obstetrical cases requiring massive transfusion protocol. TXA 
is recommended to be given in round three of obstetrical hemorrhage cases (1 gram 
intravenously over 10 minutes). (15). The authors called for more research to clarify the role and 
timing of administration of the drug in high risk obstetrical populations. Lastly, the 2015 Cochrane 
review of more than 3,000 obstetrical patients given TXA showed reduction in bleeding with no 
increase in adverse events including thromboembolism (16). 
To date, TXA has not been studied in the particular population of patients requiring cesarean 
hysterectomy for placenta previa or accreta. This inexpensive, low risk medication has potential 
to greatly reduce perioperative morbidity and cost when used in a uniquely high risk obstetrical 
population.  
Hypothesis  
We predict tranexamic acid will reduce intraoperative bleeding associated with cesarean 
hysterectomy in patients with suspected placenta accreta compared to placebo. We aim to 
perform a pilot study showing a 25% reduction in estimated blood loss versus placebo.  
Methods  
Study design: This pilot study will be conducted as a randomized, placebo-controlled, double 
blind trial in the CRMC obstetrical department. The subjects will be recruited from outpatient 
clinics by the principal investigator or co-investigators during their routine antenatal care. Study 
consent will be secured during a routine antepartum outpatient visit, or sometimes during an 
antenatal admission to Labor and Delivery. The majority of patients at CRMC and CCMC with 
suspected placenta accreta are referred to the perinatologists at the Prenatal Diagnostic Center, 
and we anticipate most patients will be recruited from this practice. We will not attempt to recruit 
new patients who are in active labor, or those with medical acuity who require immediate 
intervention. 
Study population: A consequence of studying pregnant women is that all of our study subjects will 
represent a vulnerable population. Based on our patient demographics, we anticipate a large 
proportion of the women in our study will be of Hispanic ethnicity, and will be preterm (before 37 
weeks gestation). In general, patients with suspected placenta previa have a planned preterm 
delivery at 34-36 weeks. 
Inclusion criteria:  
- English and Spanish speaking pregnant  


 
 
 
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- Any order pregnancy (singleton, twin gestation, etc)  
- With a suspected accreta based on ultrasound or MRI imaging studies  
- All women evaluated for placenta accreta and deemed to be high risk for this disease (≥40% 
risk) (14), meaning women diagnosed with a placenta previa and greater than or equal to 2 prior c-
sections  
 
Exclusion criteria:  
- Women less than 18 years of age 
- Women with a personal history of venous or arterial thrombosis (deep vein thrombosis, 
pulmonary embolism, myocardial infarction, or stroke 
- Women with a personal history of clotting disorder, such as anti-phospholipid syndrome 
- Women who do not have a good understanding of either English or Spanish will be excluded.   
- Women with defective color vision (color-blindness) [See Appendix A] 
 
Pharmacy and Drug Delivery Protocol:  
Drug purchasing: Per CRMC policy, the pharmacy cannot charge a patient for an approved drug 
in a research protocol. However, the CRMC pharmacy regularly purchases the study drug for use 
in surgical patients. The CRMC pharmacy has agreed to purchase the study drug for the principle 
investigator (Dr. Kremer), and the studies’ grant money will be used to reimburse the pharmacy at 
cost. Each vial of 1 gram of tranexamic acid for intravenous administration costs the pharmacy 
$16.70. An initial box of ten vials has been purchased and additional boxes will be ordered after 
five patients are enrolled.  
Randomization protocol: The drug and placebo will be stored, logged, and dispensed from the 
CRMC Inpatient Pharmacy. A recruited patient will be labeled study subject number one, and so 
on, by the study investigators. The name and study number will be given to Inpatient Pharmacy. 
Inpatient Pharmacy staff will randomize the subject to treatment or placebo using a blocked 
randomization technique and a computer protocol designed with assistance from Dr. Paul Mills. 
The block size will be set at 4-6 to ensure that the number of treatment and placebo subjects are 
as close to equal as possible. Inpatient Pharmacy will assign that patient to receive drug or 
placebo prior to the scheduled surgery. The randomization assignments for each study subject 
will be located in a study binder in the research pharmacy space. Inpatient Pharmacy staff 
members will be the only unblinded study staff. The study investigators, clinicians, patient, and 
hospital staff will be blinded to treatment assignments.  
 Pharmacy and Drug Delivery Protocol:  
Drug purchasing: Per hospital pharmacy policy, the study drug must be ordered from an outside 
pharmacy. The study drug will be purchased by the investigator from a non-CRMC pharmacy 
using her DEA number and delivered to the research pharmacy technician. The online pharmacy 
will be accredited with the National Association of Boards of Pharmacy member and 
recommended by chief hospital pharmacist.  
Drug delivery: In orthopedic and cardiac surgery, 1 gram of intravenous TXA is routinely given 15 
minutes before incision time. TXA is typically prepared at CRMC by removing 20cc of fluid from a 
small IV bag of 5% dextrose in plain water and then injecting the drug into the remaining 30 cc. 
This is then delivered with an IV piggyback with the patient’s preoperative fluids. 
In our study in pregnant patients, 1 gram intravenous TXA (or placebo) will be administered 
immediately after delivery of the infant and after clamping of the umbilical cord to avoid any 
potential fetal effects. The drug will be prepared and ready to hang at the beginning of the case.  


 
 
 
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Drug preparation will include the following: Removal of 20 ml from a 50 ml bag of D5W and 
injection of 10 milliliters of 100mg/ml TXA resulting in a final total volume of 40 ml. Placebo will be 
prepared by removing 10 ml from a 50 ml bag of D5W. The final volume of the study drug and the 
placebo bags will be the same and identical in appearance. 
Anesthesia staff (physicians and nurse anesthetists) working in the trauma operating rooms will 
have an in-service about the research study and procedures at a weekly staff meeting to ensure 
proper education and compliance with study protocol. Intravenous TXA or placebo will be given to 
the randomized patients by CRMC anesthesia staff after the cord has been clamped and cut 
based on the intraoperative findings. 
All patients undergoing cesarean at high risk for accreta at CRMC have two large bore IVs placed 
preoperatively. The patient will not require an additional IV for the study drug. TXA is delivered in 
5% dextrose plain water and this can be hung as a piggyback with the patient’s intraoperative 
fluids. TXA is clear and colorless and will be visually indistinguishable from the placebo. The 
hospital pharmacy will be able to provide the placebo.  
Primary outcome: The primary endpoint will be estimated intraoperative blood loss (EBL), which 
is routinely recorded at the end of all operative cases. EBL is estimated by the operating room 
team following a discussion between the surgeon and anesthesia staff based on number of tapes 
/ sponges used, amount of fluid in suction canister, amount of blood on the floor, etc. Secondary 
endpoints will include amount of blood transfusion, preop and post operative hemoglobin levels, 
length of hospital stay, ICU admission rates and length of stay, and post-operative complications 
(DVT, PE, surgical site infection). Maternal demographic information, medical comorbidities, and 
infant outcomes (weight, Apgar scores, NICU admission) will also be recorded with chart review.  
The pilot trial is planned to last 24-36 months with possible extension if needed to meet study 
enrollment targets. All final results from the study will be submitted for publication in recognized 
peer-reviewed obstetrical journals. After completion of the pilot study, a future goal is to approach 
the Maternal Fetal Medicine Unit Network (MFMU) to organize a larger multi-center trial with 
additional academic centers (https://www.nichd.nih.gov/research/supported/Pages/mfmu.aspx). 
The MFMU is a national network established by the NIH to reduce maternal, fetal, and infant 
morbidity, and to provide the rationale for evidence-based, cost-effective obstetric practice. 
Sample Size Calculation  
Sample Size: Given the low incidence of placenta accreta at CRMC (approximately 10-15 cases 
per year), we propose performing a pilot / feasibility study that will include approximately 40 cases 
over the study period of 3 years. Prior studies using TA in elective cesarean deliveries and post-
partum hemorrhage found a 30-33% reduction in estimated blood loss (9, 12). A power analysis 
with a conservative estimate of 25% reduction in predicted blood loss constraining type I errors to 
95% and type II errors to 50% requires 29 patients in each sample given our known average and 
standard deviation of blood loss in accreta patients from the past year.  
Statistical Analysis: Categorical data will be compared using the Chi-square test.  Continuous 
variables, such as estimated blood loss, will be analyzed by comparing means using the Student 
t-test.  
Adverse Events Monitoring (and explanation of routine patient care) 
The principle investigator Dr. Kremer does not typically scrub on planned cesarean hysterectomy 
cases. These surgeries are typically performed by UCSF faculty sub-specialists, Dr. William Rich 
(oncology) or Dr. Michael O’Shaughnessy (Urogynecology). However, a coinvestigator (UCSF 


 
 
 
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resident) will be present in the operating room for all cases, and directly involved in patient care 
throughout the patient’s hospitalization.  
All UCSF generalists (including Dr. Kremer) and residents (co-investigators) will be involved in 
the post operative care of these patients. There is an “attending of the day” for Labor & Delivery 
who rounds on high risk post partum patients with the residents and directly supervises resident 
care of these patients. A resident co-investigator will closely follow the patient throughout their 
post-operative course. Standard clinical care involves a “PM check” (evening visit to see the 
patient on the day of surgery), as well as daily morning rounding by a resident and attending 
faculty. The principle investigator Dr. Kremer will be notified of all potential adverse events by 
frequent communication with the resident team and with chart review, starting on post operative 
day zero, and continuing daily throughout the length of the patient’s hospitalization.  
Patients will be called by the PI or a co-investigator 24-48 hours after discharge to evaluate for 
any clinical needs at home and to monitor for potential adverse events. Patients will be seen at 2 
and 6 weeks post operatively in clinic (if their health insurance allows this) by a resident co-
investigator and UCSF faculty which is standard for post partum / post surgical care. If a patient 
no-shows to a post partum visit, they will be called to ask them to reschedule, and a letter will be 
sent to the home address to improve follow up rates.  
Patients will not be followed beyond the 6 week post partum visit. A copy of the consent form, 
including the drug risks, will be provided to each patient in the study to be given to their primary 
care doctor for future care. 
If a significant adverse event occurs at any point during the study, the research pharmacy 
technician will be notified and that patient will be unblinded to the lead study investigator. The 
principle investigator will present the patient and adverse events to the safety monitoring 
committee for discussion and potential action in a timely fashion (within 48 hours for significant 
adverse events (blood clot, patient death) and within one week for minor adverse events (rash, 
nausea/vomiting).  
Risks to Human Subjects 
The proposed research activities qualify as Human Subjects Research and meet the definition of 
clinical research, as described fully below. 
Potential Risks: Because TXA inhibits fibrinolysis, it carries a theoretical risk of thrombosis 
especially in patients with a previous history of thrombosis. However, large systematic reviews of 
randomized clinical trials for TXA use in elective surgical patients show no significant increase in 
the incidence of myocardial infarction, stroke, DVT, or pulmonary embolus (13). Furthermore, 
although pregnancy and the post partum period represent a hypercoagulable state, the risks of 
thrombosis in pregnancy are comparable to that of the orthopedic surgical population, in which 
TXA has well documented safety. TXA so far has not been shown to have any adverse effects in 
existing clinical trials involving pregnant women, and is currently being investigated in several 
large international trials in pregnant and post partum women to evaluate its promise in the 
treatment of post partum hemorrhage. 
Please see Appendix A for the Lexicomp drug monograph with on and off label dosing, and risks 
of adverse events. 
Breastfeeding: TXA is category B in pregnancy with no evidence of adverse events in pregnancy 
in animal studies. For comparison, TXA is safer than Tylenol use, which is category C with some 
evidence for adverse events in animal studies. TXA is compatible with breastfeeding. 


 
 
 
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Standard of Care: The current standard of care for patients with suspected accreta is to perform 
cesarean delivery at a tertiary care hospital with experienced surgical teams.  Planned late 
preterm delivery at 34-36 weeks gestation is recommended. Patients are expected to have two 
large bore IVs placed and be typed and crossed for transfusion, with the ability to activate a 
massive transfusion protocol if needed. Depending on surgeon preference, preoperative 
prophylactic placement of balloons in the arteries leading to the uterus to attempt to lower blood 
loss may also be performed. Research participants will be receiving the standard of care 
regardless of whether they choose to participate in the study. By choosing to participate, a 
patient’s regular treatment plan for placenta previa or placenta accreta is completed in addition to 
the administration of study drug at the time of surgery.  
Confidentiality and Privacy: The patients’ information will be accessed through electronic charts 
maintained by CRMC Health Information Management.  The patients will only be identified by a 
non-identifying code assigned to their medical record number. This data will be stored on a 
password protected Excel spreadsheet, accessible only to IRB approved investigators, and 
maintained on the UCSF-Fresno secure server.  
Data Security: The data will be saved on an Excel spreadsheet and the patients will only be 
identified by the non-identifying code.  Protected health information will not leave the study site 
and only IRB approved investigators would have access to it. Any data leaving the secure study 
site or seen by investigators not approved by the IRB will be de-identified. 
Conflicts of Interest  
The PI has no conflicts of interest to report.  
Funding 
A research grant from CCFMG was awarded to assist with the completion of this project. The final 
budget is attached. The grant will assist with remuneration of study subjects, support staff, and 
statistical support. The study investigators will not receive any payment through the grant. 
References 
1. O'Brien JM, Barton JR, Donaldson ES. The management of placenta percreta: 
conservative and operative strategies. Am J Obstet Gynecol. 1996;175(6):1632. 
2. Knuttinen MG, Jani A, Gaba RC, Bui JT, Carrillo TC. Balloon Occlusion of the Hypogastric 
Arteries in the Management of Placenta Accreta: A Case Report and Review of the Literature. 
Semin Intervent Radiol. 2012 Sep; 29(3): 161–168. 
3. Binz S, McCollester J, Thomas S, Miller J, Pohlman T, Waxman D, Shariff F, 
Tracy R, Walsh M. CRASH-2 Study of Tranexamic Acid to Treat Bleeding in Trauma 
Patients: A Controversy Fueled by Science and Social Media. J Blood Transfus. 
2015;2015:874920.   
4. Tengborn L, Blombäck M, Berntorp E. Tranexamic acid--an old drug still going 
strong and making a revival. Thromb Res. 2015 Feb;135(2):231-42. doi: 
10.1016/j.thromres.2014.11.012. Epub 2014 Nov 20. Review. PubMed PMID: 25559460. 
5. Verdun, N. Hemostatic Products CDER. FDA. 
http://www.fda.gov/downloads/medicaldevices/newsevents/workshopsconferences/ucm41490
2.pdf Accessed 12/15/2015. 
6.  Henry J, McFarland A. The effectiveness of tranexamic acid at reducing 
postoperative blood loss following cesarean section: a systematic review of 
quantitative evidence protocol. JBI Database System Rev Implement Rep. 2015 Jul 
17;13(6):72-81.   


 
 
 
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7. Wang HY, Hong SK, Duan Y, Yin HM. Tranexamic acid and blood loss during and 
after cesarean section: a meta-analysis. J Perinatol. 2015 Oct;35(10):818-25. 
8. Abdel-Aleem H, Alhusaini TK, Abdel-Aleem MA, Menoufy M, Gülmezoglu AM. 
Effectiveness of tranexamic acid on blood loss in patients undergoing elective 
cesarean section: randomized clinical trial. J Matern Fetal Neonatal Med. 2013 
Nov;26(17):1705-9.  
9. Sentilhes L, Daniel V, Darsonval A, Deruelle P, Vardon D, Perrotin F, Le Ray 
C, Senat MV, Winer N, Maillard F, Deneux-Tharaux C. Study protocol. TRAAP - 
TRAnexamic Acid for Preventing postpartum hemorrhage after vaginal delivery: a 
multicenter randomized, double-blind, placebo-controlled trial. BMC Pregnancy 
Childbirth. 2015 Jun 14;15:135.   
10. World Maternal Antifibrinolytic Trial (WOMEN). London School of Hygiene and Tropical 
Medicine. Ongoing clinical trial scheduled to end in 2016. 
https://clinicaltrials.gov/ct2/show/NCT00872469 
11. Testing of the Drug Tranexamic Acids as Prophylaxis of Bleeding in Benign Surgical 
Removal of the Uterus (PeTraH). Completed 2015. Hillerod Hospital, Denmark. 2013-2014 
https://clinicaltrials.gov/ct2/show/record/NCT01940419?term=lysteda&rank=8  
12. Maged, A, Helal O, Elsherbini M, Eid M, Elkomy R, Dahab S, Elsissy M. A randomized 
placebo-controlled trial of preoperative tranexamic acid among women undergoing elective 
cesarean delivery. International Jounral of Gynecology and Obstetrics. 2015 Dec;131(3):265-
8. 
13. Ker K, Edwards P, Perel P, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, et al. 
Effects of tranexamic acid on surgical bleeding: systematic review and cumulative meta-
analysis. BMJ. 2012;344:e3054.  
14. Silver RM, Landon MB, Rouse DJ, Leveno KJ, Spong CY, Thom EA, Moawad AH, Caritis 
SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, O'Sullivan 
MJ, Sibai B, Langer O, Thorp JM, Ramin SM, Mercer BM, National Institute of Child Health 
and Human Development Maternal-Fetal Medicine Units Network. Maternal morbidity 
associated with multiple repeat cesarean deliveries. Obstet Gynecol. 2006;107(6):1226.  
15. Pacheco, LD, Saade GR, Constantine MM, Clark SL, Hankins GD. An update on the use 
of massive transfusion protocols in obstetrics. American Journal of Obstetrics and 
Gynecology. 2016 Mar14(3):340-4. 
16. Novikova N, Hofmeyr GJ, Cluver C. Tranexamic acid for preventing postpartum 
haemorrhage. Cochrane Database of Systematic Reviews 2015, Issue 6. Art. No.: 
CD007872. 

ICF_000.pdf: 
Consent Version date: 9/7/2016 
 
Participant Initials:________ 
 
Page 1 of 11  
 
 
Mallory Kremer MD  
155 North Fresno Street, Suite 233 
Fresno, CA 93701-2302 
559-499-6549 
 
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO -- FRESNO 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
 
Study Title:  Intraoperative Administration of Tranexamic Acid for Placenta Previa and Accreta 
Study (TAPPAS): A Randomized, Placebo-controlled Trial 
 
This is a medical research study led by Dr. Kremer from the UCSF Fresno Department of OBGYN. 
Dr. Kremer and/or her research team will explain this study to you. 
 
Medical research studies include only people who choose to take part. Take your time to make 
your decision about participating. You may discuss your decision with your family and friends and 
with your health care team. If you have any questions, you may ask your study doctor.  
 
You are being asked to take part in this study because you (a) have a suspected accreta based on 
imaging studies (ultrasound or MRI study), or (b) are at high risk for having a placenta accreta (for 
example, at least two prior c-sections with a low lying placenta previa).  Placenta accreta is a 
condition in which the placenta abnormally invades or grows into the uterine wall.  Placenta previa 
is a condition in which the placenta is lying unusually low in the uterus, next to or covering the 
cervix. 
  
Why is this study being done?  
Surgeries done for patients with placenta previa or accreta are high risk and involve a higher 
amount of blood loss than normal c-sections. Often, placenta accreta requires complete removal 
of the uterus (hysterectomy) after performing a c-section to control bleeding. Today, there are no 
medications commonly used to reduce blood loss in patients with these high risk surgeries.    
 
The purpose of this study is to determine if intravenous tranexamic acid (TA) is effective for 
reducing blood loss during surgical procedures in women at high risk for hemorrhage due to 
placenta previa or placenta accreta. TA is not currently FDA approved to treat blood loss during C-
sections; however, it is commonly used in other types of surgery for patients who are expected to 
have a large blood loss, such as hip replacements or open heart surgery.  
 
The current standard of care for patients at high risk for having a placenta accreta or patients 
suspected of having a placenta acreta is to perform the surgery at a tertiary care hospital with 
experienced surgeons and operating room teams, with access to blood products if transfusion is 
needed.  Sometimes, a surgeon will also request placement of balloons in the arteries leading to 
the uterus to attempt to lower blood loss. You will be receiving the standard of care regardless of 
whether you choose to participate in the study.  


Consent Version date: 9/7/2016 
 
Participant Initials:________ 
 
Page 2 of 11  
 
 
 
How many people will take part in this study? 
Placenta previa with multiple prior c-sections, and placenta accreta is very rare. About 60 people 
will take part in this study.  
 
What will happen if I take part in this research study? 
All study procedures will be done at Community Regional Medical Center. You will be randomized 
into one of the study groups described below. Randomization means you are put into a group by 
chance. The investigators will randomize you electronically into one of the groups. Neither you nor 
your doctor can choose the group you will be in. You will have an equal chance of being placed in 
any group.   
 
• If you are in group 1: You will be given 1 gram of intravenous TA in your IV immediately 
after delivery of the infant. 
• If you are in group 2: You will be given a placebo (no study drug) in your IV immediately 
after delivery of the infant. 
 
 
Study Plan 
Another way to find out what will happen to you during the study is to read the chart below. Start 
reading at the top and read down the list, following the lines and arrows.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Start Here 
Pregnant with suspected accreta or at high risk for 
accreta (two prior C-sections + placenta previa) 
Randomized 
(You will be in Group 1 or Group 2) 
Group 2 
• Given placebo immediately 
following delivery of infant 
Group 1 
• Given 1 gram of TA 
immediately following 
delivery of infant 
Consented 
(Agree to be in the study during your prenatal care) 


Consent Version date: 9/7/2016 
 
Participant Initials:________ 
 
Page 3 of 11  
 
 
 
After your surgery, study investigators monitor you throughout your hospital stay and follow up 
with you at your routine post-operative visits.  
 
How will information about me be kept confidential? 
 
Information will be collected from your medical records. Only study-approved investigators, the 
Community Medical Centers’ Institutional Review Board, or federal and state regulatory groups 
will be able to look at or copy medical records. Study records that identify you will be kept 
confidential and you will be assigned a unique code number. 
 
Some information from your medical records will be collected and used for this study. If you do 
not have a medical record, one will be created for you. Your signed consent form will be added to 
your medical record. Therefore, people involved with your future care and insurance may become 
aware of your participation and of any information added to your medical record as a result of 
your participation. 
 
How long will I be in the study? 
Participation in the study begins after consent and concludes with your last post-operative visit. 
The study drug, however, will only be administered once during your surgery. All other study 
related follow ups will be during your routine hospital visits.  
 
What are my responsibilities? 
As a research participant you will be asked to follow the instructions listed in this informed 
consent form, and notify the study doctor if any information regarding your health or availability 
to participate in the study changes. 
 
Can I stop being in the study? 
Yes. You have the right to stop being in the study, without loss of benefits to which you are 
otherwise entitled. This means that you can decide to stop at any time. Tell the study doctor if you 
are thinking about stopping or decide to stop. She will tell you how to stop your participation 
safely.  
 
What side effects or risks can I expect from being in the study?  
 
Below are the risks of participating in this study:  
1. Stress or worry from participating in a study. Please remember at any time you can choose 
to stop participation.  
2. Risk of Randomization: You will be assigned between two different treatment groups by 
chance, and the treatment you receive may prove to be less effective or have more side 
effects than the other study group. 


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3. Risk of placebo: If you are in the group that receives placebo, your surgical procedure will 
proceed without the additional study drug treatment.  
4. Unknown risks: The experimental treatments may have side effects that no one knows 
about yet. The researchers will let you know if they learn anything that might make you 
change your mind about participating in the study. 
Everyone taking part in the study will be watched carefully for any side effects. Tranexamic Acid 
(TA) medicine may cause some unwanted side effects. Although not all of these side effects may occur, if 
they do occur they may need medical attention. Many side effects go away shortly after the drugs are 
stopped, but in some cases side effects may be serious, long lasting, life threatening or result in death. 
You should talk to your study doctor about any side effects you experience while taking part in the study. 
For more information about your condition and research-related injury or about this study you may contact 
Dr. Kremer at 559-499-6549. 
Tranexamic acid (TA) is safe and has been studied before in pregnant and postpartum women to reduce 
bleeding after vaginal deliveries and in women with cesarean sections.  All pregnant and recently pregnant 
(also known as post partum) women have an increased risk of blood clots in the legs or lungs. In prior 
studies in these women, TA did not increase the risk of blood clots in the legs or lungs (deep vein 
thrombosis or pulmonary embolism) beyond your baseline risk. However, the drug is not thought to be safe 
to use in patients who have active (pre-existing) blood clots in the legs or lungs (deep vein thrombosis or 
pulmonary embolism) or in women with blood clotting disorders or in women with active bleeding in the 
brain. These women will not be able to participate in the study. The drug also can have a rare side effect of 
changes in color vision. For this reason, women who are already color-blind cannot participate in the study. 
Tranexamic acid can be passed into breast milk in very small concentrations but it is safe to participate in 
the study if you plan to breastfeed or pump. About 1% of the drug levels in your blood can be detected in 
breast milk one hour later. The drug has a short “half life”, which means that it is present in your body for a 
short period of time, and is present at significant levels in your blood for only about 2-11 hours after the 
last dose is given.  
Check with your doctor immediately if any of the following side effects occur: 
 
Infrequent: (percentages for how often these side effects occur are not available by the drug manufacturer) 
• 
Diarrhea, nausea, or vomiting  
• 
Low blood pressure  
• 
Inflammation of skin caused by an allergic reaction  
• 
Blurred vision  
• 
Giddiness 
Rare (occuring less than 1% of the time):  
• 
Severe allergic reaction (anaphylaxis)  
• 
Problems with eyesight (color vision changes)  
• 
Blood Clots in the legs or lungs  


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• 
Seizure  
• 
Dizziness or lightheadedness, decreased alertness  
• 
Problems with the kidney or the ureter (due to blood clot formation) 
 
For more information about the risks and side effects, ask your study doctor.  
 
Are there benefits to taking part in the study?  
If tranexamic acid is effective in reducing blood loss, the benefit would be less blood loss, less need 
for blood transfusion, and possibly fewer other complications related to blood loss in surgery 
(bleeding disorders, low temperature). Also, even if the drug is not effective or helpful to you, the 
benefit for all participants is to increase our knowledge about ways to treat heavy operative 
bleeding from placenta previa or placenta accreta for women in the future.  
 
If you are in the group that receives TA and it proves to treat your condition more effectively than 
the placebo, you may benefit from participating in the study, but this cannot be guaranteed.  
 
What other choices do I have if I do not take part in this study?  
If you wish not to take part in the study, you will receive the standard care for your condition 
without being in the study and will not lose any benefits to which you are otherwise entitled. 
 
 To end your participation in this study, you must contact the study doctor at the contact 
information listed on page 1 of this informed consent form.  Your participation in this study is 
voluntary.  If you do join the study, you may leave the study at any time.  Your decision to 
participate will not change your relationship with your doctor or the hospital. 
 
The study doctor in charge of the research study can remove you from this study without your 
consent for any reason, including, but not limited to: 
a. 
His/her judgment that any condition or circumstance may jeopardize your welfare such as  
increased risk, change in potential benefit, or the integrity of the study. 
b. 
Your failure to follow the instructions of the study staff. 
c. 
If the study is stopped by the sponsor, study doctor, IRB, or FDA. 
 
Will my medical information be kept private? 
We will take every precaution to make sure that the personal information in your medical record is 
kept private and secure.  However, we cannot guarantee complete privacy. Your personal 
information may be given out if required by law. If information from this study is published or 
presented at scientific meetings, your name and other personal information will not be used.  
 
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• UCSF’s Committee on Human Research 


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• Community Medical Centers’ Institutional Review Board (a committee charged with the 
protection of human subjects in research) 
• The University of California 
• Food and Drug Administration 
• Office for Human Research Protections 
• Department of Health and Human Services 
• Community Medical Centers 
 
What are the costs of taking part in this study? 
The will be no additional cost to you for participation. You will not be responsible for the cost of 
the study drug. You will have to pay for any costs not covered by your health insurer.  
 
Will I be paid for taking part in this study? 
You will receive a $20 gift card for your participation after you consent and are enrolled in the 
study. 
 
Are there any financial conflicts on the part of the researchers? 
The study was awarded a grant to cover costs of conducting the study.  The researchers are not 
getting financial compensation for this study. There is no financial conflict of interest. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, Dr. Kremer if you feel that you have been injured 
because of taking part in this study. You can tell the doctor in person or call her at (559) 499-6549.  
 
Treatment and compensation for Injury: If you are injured as a result of being in this study, 
the University of California will provide necessary medical treatment. The costs of the 
treatment may be billed to you or your insurer just like any other medical costs, or covered 
by the University of California, depending on a number of factors. The University of 
California does not normally provide any other form of compensation for injury. For further 
information about this, you may call the office of the Committee on Human Research at 
415-476-1814. You may also contact the Community Medical Centers IRB office at (559) 
499-6653 for further information. 
 
What are my rights if I take part in this study? 
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. Leaving the study will not affect your medical care. You can still get your medical care 
from our institution.  
 
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study.  
 


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In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.  
 
Who can answer my questions about this study? 
You can talk to your study doctor about any questions, concerns, or complaints you have about 
this study. For information about your disease, about research – related injury, or about this study, 
you may contact Dr. Kremer at (559) 499-6549. For information about your rights as a research 
subject, you may contact the Chair of Community Medical Centers (CMC) Institutional Review 
Board (IRB) at (559) 499-6653. 
 
If you wish to ask questions about the study or your rights as a research participant to someone 
other than the researchers or if you wish to voice any problems or concerns you may have about 
the study, please call the Office of the Committee on Human Research at (415) 476-1814 or the 
CMC IRB at (559) 499-6653.  
 
For additional information about this clinical trial you can visit www.clinicaltrials.gov. 
ClinicalTrials.gov is a website that provides information about clinical trials. 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. 
 
CONSENT 
You have been given a copy of this consent form and the Experimental Subject’s Bill of Rights to 
keep.  You will be asked to sign a separate form authorizing access, use, creation, or disclosure of 
health information about you. 
 
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to participate or to 
withdraw at any point in this study without penalty or loss of benefits to which you are otherwise 
entitled.  
 
If you wish to participate in this study, you should sign below.  
 
 
 
__________________________________ 
 
 
 
_________________ 
Printed Name of Subject 
 
 
 
 
 
CMC Medical Record # 
 
 
__________________________________ 
 
 
 
_________________ 
Subject’s Signature for Consent 
 
 
 
 
Date Signed/Time 
 
 
 
 


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Participant Initials:________ 
 
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__________________________________ 
 
 
 
Printed Name of Witness  
 
 
 
 
 
 
 
 
 
 
__________________________________ 
 
 
 
_________________ 
Witness Signature  
 
 
 
 
 
 
Date Signed/Time 
 
 
 
Investigator’s Signature Below 
 
 
 
__________________________________ 
 
 
 
_________________ 
Printed Name of Person Obtaining Consent  
 
 
Date Signed/Time 
 
 
__________________________________ 
Signature of Person Obtaining Consent  
 
 
__________________________________ 
 
 
 
_________________ 
Investigator Printed Name 
 
 
 
 
 
Date Signed/Time 
 
 
__________________________________ 
Investigator Signature 
 
 
CMC’s Interpreter Statement:  
In the event that an interpreter is needed: I have accurately and completely read the  
 
foregoing document to: __________________________________ in _______________ 
 
 
 
        (Patient or Legal Representative Name)     (Language Used) 
 
She understands all terminology/conditions, acknowledges her agreement by signing the 
document in my presence.  
 
__________________________________    
 
 
 
_____________ 
Printed Name/Signature of Interpreter 
 
 
 
 
Date Signed/Time 
 
 
 
 


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CALIFORNIA EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
California law requires that any person asked to take part as a subject in research involving a 
medical experiment, or any person asked to consent to such participation on behalf of another, is 
entitled to receive the following list of rights written in a language in which the person is fluent.  
This list includes the right to: 
 
1. Be informed of the nature and purpose of the experiment. 
2. Be given an explanation of the procedure to be followed in the medical experiment and 
any drug or device to be utilized.   
 
3. Be given a description of any attendant discomforts and risks reasonably to be expected 
from the experiment.   
4. Be given an explanation of any benefits to the subject reasonably to be expected from the 
experiment, if applicable. 
5. Be given a disclosure of any appropriate alternative procedures, drugs, or devices that 
might be advantageous to the subject, and their relative risks and benefits.   
6. Be informed of the avenues of medical treatment, if any, available to the subject after the 
experiment if complications should arise.   
7. Be given an opportunity to ask any questions concerning the experiment or the procedures 
involved. 
8. Be instructed that consent to participate in the medical experiment may be withdrawn at 
any time and the subject may discontinue participation in the medical experiment without 
prejudice. 
9. Be given a copy of the signed and dated written consent form. 
10. Be given the opportunity to decide to consent or not to consent to a medical experiment 
without the intervention of any element of force, fraud, deceit, duress, coercion, or undue 
influence on the subject’s decision. 
 
For questions about patient rights, contact the Chairman of the Institutional Review Board at 
Community Medical Centers at (559) 499-6552.   
 
I have carefully read the information contained above and I understand fully my rights as a 
potential subject in a medical experiment involving people as subjects.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name/ Signature (Subject) 
 
 
 
 
Date/Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name/ Signature (Witness)  
 
 
 
Date/Time 
 


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USE AND DISCLOSURE OF YOUR PROTECTED HEALTH INFORMATION 
 
Protected Health Information is any personal health information through which you 
can be identified. A decision to participate in this research means that you agree to 
the use of your health information for the purposes explained in this consent form.  
By signing this form, you are authorizing the use and disclosure of your health 
information collected in connection with your participation in this research study. 
Your information will only be used in accordance with the provisions of this consent 
form and applicable law. 
 
Your health information related to this study, including your entire medical record, 
may be used or disclosed in connection with this research study. Study records that 
identify you will be kept confidential as required by law. Except when required by 
law, you will not be identified by name, SS#, address, phone#, or any other direct 
personal identifier in study records disclosed outside of the Community Medical 
Centers (CMC). For records disclosed outside of CMC, you will be assigned a unique 
code number. The key to the code will be kept in a locked file in the office of the 
Principal Investigator, Dr. Kremer. 
 
Representatives of the following groups are authorized to use and/or disclose your 
health information in connection with this research study:  
The principal investigator, Dr. Kremer, her research team, and all Sub-Investigators  
The Community Medical Centers Institutional Review Board  
The University of California 
Community Medical Center 
 
The parties listed in the preceding paragraph may disclose your health information 
to the following persons and organizations for their use in connection with this 
research study: 
The Office of Human Research Protections   
Department Of Health and Human Services 
Federal and State Regulatory Groups  
Food and Drug Administration 
 
EXPIRATION DATE OR EVENT FOR THE RETENTION OF RECORDS 
The study results will be retained in your research record for at least six years or 
until after the study is completed, whichever is longer.  At that time either the 


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research information not already in your medical record will be destroyed or 
information identifying you will be removed from such study results at Community 
Medical Centers.  Any research information in your medical record will be kept 
indefinitely. 
 
VOLUNTARY PARTICIPATION 
 
Your participation is voluntary and you may choose not to participate in this 
research study or withdraw your consent or authorization for the use and disclosure 
of your health information at any time. Your choice will not at any time affect the 
commitment of your health care providers to administer care and there will be no 
penalty or loss of benefits to which you are otherwise entitled. If you decide to end 
your participation in the study, please notify the researcher(s) in writing. 
 
If you have questions or concerns regarding your privacy and the use of your 
personal health information, please contact the Privacy Officer, at 559-459-2742.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name/ Signature (Subject) 
    
 
 
 
Date/Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name/ Signature (Witness) 
 
 
 
 
Date/Time