Clinical trial NCT04635839
Conditions: Pregnancy Related Antepartum DVT
Keywords: Thromboprophylaxis Antepartum admission Heparin
Sponsor: University of California, Los Angeles
Start date: 2020-12-15; Completion date: 2022-05-01
Enrollment: 46 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a randomized control trial to compare gestational age-based dosing with standard dosing of unfractionated heparin for thromboprophylaxis of hospitalized antepartum patients. The investigators aim to determine the effect of dosing on receipt of neuraxial anesthesia and pregnancy outcomes and evaluate the pharmacokinetics and pharmacodynamics of unfractionated heparin in pregnancy.

Detailed description:
Venous thromboembolism is one of the leading causes of maternal morbidity and mortality, and antepartum hospitalizations place pregnant patients at an even higher risk of developing thromboembolism. As a result, there is an increased emphasis on administering pharmacologic thromboprophylaxis for antepartum patients with prolonged hospitalizations. Previously, standard dosing of unfractionated heparin was widely adopted for thromboprophylaxis in the pregnant population. However, due to a suspected altered metabolism of unfractionated heparin in pregnancy resulting in a decrease response, the American College of Obstetricians and Gynecologists (ACOG) currently recommends considering gestational age-based dosing for unfractionated heparin for thromboprophylaxis in pregnancy with standard dosing as an alternative option. The data supporting altered dosing is very limited. In addition, increased dosing of heparin may result in challenges in anesthetic management, potentially limiting the receipt of neuraxial anesthesia resulting in increased need for general anesthesia associated with both increased maternal and fetal risks. The potential effects of higher prophylactic unfractionated heparin dosing in pregnant patients need to be further explored before being widely adopted for inpatient antepartum thromboprophylaxis. The investigators propose this study to provide a direct comparison of gestational age-based unfractionated heparin dosing to standard dosing of unfractionated heparin for pharmacologic thromboprophylaxis of hospitalized antepartum patients.

Arms: arm 1: Standard dose of unfractionated heparin arm 2: Dose of unfractionated heparin based on trimester of pregnancy
Interventions: intervention 1: Standard Dose of Unfractionated Heparin intervention 2: Gestational Age-Based Dose of Unfractionated Heparin
Intervention descriptions: intervention 1: 5,000 units subcutaneous unfractionated heparin every 12 hours intervention 2: * First trimester (\< 14 weeks of gestation): 5,000 units subcutaneous unfractionated heparin every 12 hours
* Second trimester (14-28 weeks of gestation): 7,500 units subcutaneous unfractionated heparin every 12 hours
* Third trimester (\> 28 weeks of gestation): 10,000 units subcutaneous unfractionated heparin every 12 hours

Protocol documents:
Prot_004.pdf: 
Title of Study: Heparin Prophylaxis Dosing for Antepartum Hospitalizations (HEPDOSE) 
 
NCT Number: NCT04635839 
 
Document Date: November 4, 2020 
 
Document: Study Protocol  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Principal Investigators: 
Thalia Mok, MD 
Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of 
California, Los Angeles 
 
Rashmi Rao, MD 
Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of 
California, Los Angeles 
 
Collaborators: 
Krista Cascia, MD 
Department of Anesthesiology, University of California, Los Angeles 
 
Richard Hong, MD 
Department of Anesthesiology, University of California, Los Angeles 
 
Neil S. Silverman, MD 
Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine  
Center for Fetal Medicine and Women’s Ultrasounds, Los Angeles, California 
 
Cristianna Vallera, MD 
Department of Anesthesiology, University of California, Los Angeles 
 
 


LIST OF ABBREVIATIONS 
AE 
adverse event 
aPTT 
CFR 
activated partial thromboplastin time 
Code of Federal Regulations 
CRF 
case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
PI 
Principal Investigator 
SAE 
VTE 
ACOG 
NPMS 
serious adverse experience 
venous thromboembolism 
American College of Obstetricians and Gynecologists 
National Partnership for Maternal Safety 
 
 


PROTOCOL SYNOPSIS 
TITLE 
Randomized Control Trial of Unfractionated Heparin Dosing for 
Thromboprophylaxis of Hospitalized Antepartum Patients   
 
 
SPONSOR 
Rashmi Rao, MD 
 
 
FUNDING 
ORGANIZATION 
N/A 
NUMBER OF SITES 
1  
 
 
RATIONALE 
VTE is one of the leading causes of maternal morbidity and mortality, 
and antepartum hospitalizations place pregnant patients at an even 
higher risk of developing thromboembolism. As a result, there is an 
increased emphasis on administering pharmacologic 
thromboprophylaxis for antepartum patients with prolonged 
hospitalizations. Previously, standard dosing of unfractionated heparin 
was widely adopted for thromboprophylaxis in the pregnant 
population. However, due to a suspected altered metabolism of 
unfractionated heparin in pregnancy resulting in a decrease response, 
the American College of Obstetricians and Gynecologists (ACOG) 
and National Partnership for Maternal Safety (NPMS) currently 
recommends considering gestational age-based dosing for 
unfractionated heparin for thromboprophylaxis in pregnancy with 
standard dosing as an alternative option. The data supporting altered 
dosing is very limited. In addition, increased dosing of heparin may 
result in challenges in anesthetic management, potentially limiting the 
receipt of neuraxial anesthesia resulting in increased need for general 
anesthesia associated with both increased maternal and fetal risks. The 
potential effects of higher prophylactic unfractionated heparin dosing 
in pregnant patients need to be further explored before being widely 
adopted for inpatient antepartum thromboprophylaxis. We propose 
this study to provide a direct comparison of gestational age-based 
unfractionated heparin dosing to standard dosing of unfractionated 
heparin for pharmacologic thromboprophylaxis of hospitalized 
antepartum patients. 
 
 
STUDY DESIGN 
This is a single center, open label, randomized control trial.   
 
 
PRIMARY 
OBJECTIVE 
Compare gestational age-based dosing to standard dosing of 
unfractionated heparin for thromboprophylaxis of pregnant patients 
with prolonged hospitalizations and determine its effect on receipt of 
neuraxial anesthesia and pregnancy outcomes. 
 
 
SECONDARY 
OBJECTIVES 
Evaluate pharmacokinetics and pharmacodynamics of unfractionated 
heparin in pregnancy. 


a) Determine the frequency of adjusted unfractionated heparin dosing 
based on elevated activated partial thromboplastin time (aPTT) values 
and assess maternal characteristics associated with elevated aPTT 
values. 
b) Determine the appropriate dosing of unfractionated heparin for 
pharmacologic thromboprophylaxis of hospitalized antepartum 
patients. 
 
 
NUMBER OF 
SUBJECTS 
46 
 
 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
• At least 18 years of age 
• Speak English or Spanish 
• Antepartum admission for at least 72 hours at Ronald Reagan 
UCLA Medical Center  
• Provides informed consent for study participation  
 
Exclusion Criteria: 
• Active or threatened antenatal bleeding 
• Disseminated intravascular coagulation  
• Risk of imminent delivery (delivery within 12 hours) 
• Thrombocytopenia (platelet count < 100 x 109) 
• Elevated baseline aPTT (> 36.2 seconds) 
• Concern for hemolysis, elevated liver enzymes, low platelet 
count (HELLP) syndrome  
• Congenital bleeding disorders (hemophilias)  
• Receiving therapeutic or prophylactic anticoagulation 
(unfractionated heparin, low molecular weight heparin, oral 
anticoagulants) for alternative indication (e.g., acquired or 
inherited thrombophilia, history of VTE) 
• History of heparin-induced thrombocytopenia (HIT)  
• SARS-CoV-2 positive   
• Cognitive impairment, psychiatric instability, or language 
barriers that limit their ability to provide informed consent 
• Presence of a condition or abnormality that in the opinion of 
the Investigator would compromise the safety of the patient or 
the quality of the data. 
 
 
 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Gestational age-based unfractionated heparin dosing: 
First trimester ( 13w6d): 5,000 units subcutaneous unfractionated 
heparin every 12 hours 


Second trimester (14w0d – 27w6d): 7,500 units subcutaneous 
unfractionated heparin every 12 hours  
Third trimester ( 28w0d): 10,000 units subcutaneous unfractionated 
heparin every 12 hours  
Duration: throughout hospitalization (until discharge or delivery) 
 
 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Standard unfractionated heparin dosing (comparator): 5,000 units 
subcutaneous unfractionated heparin every 12 hours 
Duration: throughout hospitalization (until discharge or delivery) 
 
 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on study for the duration of their inpatient admission.  
The total duration of the study is expected to be approximately 18 
months (16 months for subject recruitment and 2 months for final 
subject follow-up).  
 
 
CONCOMMITANT 
MEDICATIONS 
Allowed: All except for prohibited medications (listed below)  
Prohibited: low molecular weight heparin, warfarin, oral 
anticoagulants  
 
 
PRIMARY ENDPOINT 
Elevated serum aPTT value above the normal range (> 36.2 
seconds) 
SECONDARY 
ENDPOINTS 
● Diagnosis of venous thromboembolism (pulmonary embolism 
and/or deep venous thromboembolism) 
● Nonreceipt or delay of neuraxial anesthesia due to unfractionated 
heparin defined as inability to receive neuraxial anesthesia due to 
an elevated aPTT value or because the subject received heparin  
● Receipt of general anesthesia due to unfractionated heparin  
● Delay in timing of delivery due to unfractionated heparin defined 
as presence of an indication to proceed with delivery via cesarean 
delivery or induction of labor but this does not immediately occur 
due to an elevated aPTT value or because the subject received 
heparin 
● Mode of delivery  
● Estimated blood loss at time of delivery 
● Receipt of blood transfusion  
● CBC for hemoglobin and platelet count (to be assessed weekly 
while receiving unfractionated heparin) 
● Anti-Xa levels (to be assessed with aPTTs while receiving 
unfractionated heparin) 
● Goal anti-Xa level achieved (0.2-0.5 IU/mL) 
● Number of times adjustment in dose made 
● Development of side effects from heparin administration (e.g 
bruising, epistaxis) 
● Neonatal outcomes  


o Gestational age at delivery 
o Birthweight 
o 1 minute and 5 minute APGAR scores 
o Cord blood gas values: umbilical artery pH, umbilical artery 
CO2, umbilical artery base excess 
o NICU admission  
o Neonatal death  
SAFETY 
EVALUATIONS 
● Incidence of adverse events 
 
 
STATISTICS 
Primary Analysis Plan 
Analysis of the primary endpoint of whether or not there was an 
elevation in aPTT in each dosing group will be performed with a Chi-
squared test. Multivariate logistic regression analysis will be 
performed to determine which factors were associated with an 
elevated aPTT value. Comparison of maternal demographics, baseline 
characteristics, additional maternal outcomes, and neonatal outcomes 
between the two groups will be analyzed using Student’s t-test for 
parametric data, Wilcoxon signed-rank test for nonparametric data, 
and Chi-squared or Fisher’s exact test for comparison of proportions. 
Descriptive statistics will be performed to summarize which dose 
resulted in a normal aPTT value and anti-Xa within goal range. 
Statistical significance will be set at a p-value of < 0.05 or 95% 
confidence interval not overlapping.  
Rationale for Number 
of Subjects 
Assuming 40% of patients receiving gestational age-based dosing and 
3% receiving standard dosing have an elevated aPTT value, a sample 
size of 36 women (18 in each arm) would have 80% power to 
demonstrate a significant difference between the proportion of women 
with elevated aPTT values after administration. We plan to recruit 46 
(23 in each arm) to account for post-randomization drop out and lab 
sampling errors.  
 
 
 


1 BACKGROUND 
1.1 
Overview of Non-Clinical and Clinical Studies 
Venous thromboembolism (VTE) is one of the leading causes of maternal morbidity and 
mortality, accounting for 14.9% of maternal deaths in developed countries and 9.3% of maternal 
deaths in the United States according to the World Health Organization’s systematic review of 
maternal mortality.1 Antepartum hospitalizations may place pregnant patients at an even higher 
risk of developing a thromboembolism. A study in England found that the risk of VTE was 17.5-
fold higher when patients were hospitalized compared with outpatient with the risk significantly 
higher for patients hospitalized 3 days or longer.2 As a result, there has been an increased 
emphasis on considering pharmacologic thromboprophylaxis for antepartum patients with 
prolonged hospitalizations.  
 
However, the recommendations on administration of pharmacologic prophylaxis in pregnancy 
from different societies vary.3-7 Administration of routine pharmacologic prophylaxis has 
demonstrated a significant decrease in maternal mortality in the United Kingdom attributed to 
VTE.8 The National Partnership for Maternal Safety (NPMS) compiled recommendations from 
societies and reviewed the available evidence to develop a thromboembolism safety bundle with 
the aims of decreasing VTE in pregnancy and improving maternal outcomes. One of these 
recommendations is that pharmacologic thromboprophylaxis should be given to all antepartum 
patients hospitalized for at least 72 hours and not at high risk for bleeding or imminent 
childbirth.9 
 
The American College of Obstetricians and Gynecologists (ACOG) states that the preferred 
anticoagulant for pregnancy are heparin compounds, including unfractionated heparin and low 
molecular weight heparin.6 Heparin compounds do not cross the placenta and are considered safe 
in pregnancy.10-12 It is agreed upon that heparin compounds are considered first line therapy for 
anticoagulation in pregnancy. However, multiple physiological changes of pregnancy, including 
expansion of maternal blood volume, higher renal excretion of heparin, and increased non-
specific binding proteins, alter the metabolism of unfractionated heparin in pregnant patients 
compared to nonpregnant patients.13,14 There is limited data on heparin dosing in pregnancy for 
thromboembolic prophylaxis. A single study of fourteen pregnant patients on heparin 
prophylaxis for a history of thromboembolism demonstrated that the standard heparin dose of 
5,000 units administered subcutaneously (SC) twice daily was inadequate to achieve the desired 
anti-Xa level range in all patients.15 Although data is limited, responses to heparin in pregnant 
patients are highly variable and there is a suspected need for higher dosing with increasing 
gestational age.  
 
Standard dosing of unfractionated heparin of 10,000-15,000 units daily (5,000 units SC every 8-
12 hours) has been demonstrated to be effective for thromboprophylaxis in the surgical 
population.16 This dosing is recommended by the American College of Chest Physicians and 
widely accepted in the nonpregnant population.17 Previously, standard dosing of unfractionated 
heparin was also adopted for use in the pregnant population. However, ACOG and the NPMS 
now recommends considering gestational age-based dosing for unfractionated heparin for 
thromboprophylaxis in pregnancy (5,000-7,500 units SC every 12 hours in the first trimester, 
7,500-10,000 units SC every 12 hours in the second trimester, and 10,000 units SC every 12 


hours in the third trimester) with standard dosing of 5,000 units SC every 12 hours as an 
alternative option for hospitalized patients that may require delivery to facilitate receipt of 
neuraxial anesthesia.6, 18  
 
Increasing dosing of heparin for thromboprophylaxis presents challenges in anesthetic 
management. Various anesthesia professional organizations have provided recommendations on 
when to proceed with neuraxial anesthesia for a patient on pharmacologic thromboprophylaxis, 
based on dose and time of administration and pertinent laboratory values such as activated partial 
thromboplastin time (aPTT).19-22 At our institution, neuraxial anesthesia can be offered at 
anytime if a patient is receiving 5,000 units SC every 12 hours, but if the patient is receiving 
7,500 units-10,000 units SC every 12 hours then the anesthesiologists require at least a 6-12 hour 
interval with an aPTT value in the normal range (< 36.2 seconds) to consider neuraxial 
anesthesia.  
 
In an effort to decrease incidence of VTE and associated maternal morbidity and mortality, our 
institution has adopted the recommendations for pharmacologic thromboprophylaxis for all 
inpatient antepartum admissions over 72 hours and utilized ACOG’s gestational age-based 
dosing for unfractionated heparin. An informal/pilot review of 30 antepartum admissions 
receiving trimester based dosing of unfractionated heparin for VTE prophylaxis demonstrated 
that 40% of the patients had an abnormally elevated aPTT value with two patients being in the 
therapeutic range. One patient was unable to receive an epidural in active labor and one patient 
had a delay in her cesarean delivery due to receiving heparin prophylaxis within the 6 hour 
interval. Although increased administration pharmacologic prophylaxis is associated with a 
decreased risk of VTE, our preliminary data demonstrates that the trimester based dosing of 
unfractionated heparin may lead to elevated aPTT values, potentially limiting the receipt of 
neuraxial anesthesia. This may then lead to an increased need for general anesthesia associated 
with both increased maternal and fetal risks.  
 
To the best of our knowledge, there have been no prior studies comparing standard dosing with 
gestational age-based dosing of unfractionated heparin for VTE prophylaxis. The potential 
effects of higher prophylactic unfractionated heparin dosing need to be further explored before 
being widely adopted for inpatient antepartum thromboprophylaxis.  
2 STUDY RATIONALE 
VTE is one of the leading causes of maternal morbidity and mortality. In efforts to decrease rates 
of VTE, there is an increased emphasis on administering pharmacologic thromboprophylaxis for 
antepartum patients with prolonged hospitalizations. Due to physiological changes of pregnancy 
that may alter the metabolism of unfractionated heparin, it is suspected that dosing of 
pharmacologic thromboprophylaxis may need to be altered. ACOG’s current recommendation is 
to consider gestational age-based dosing of unfractionated heparin for hospitalized pregnant 
patients rather than standard dosing. However, there are no prior studies assessing the potential 
effects of higher dosing. Potential effects of higher dosing include limited receipt of neuraxial 
anesthesia, increased administration of general anesthesia, delayed time to delivery, and 
increased bleeding risk. We propose this study to provide a direct comparison of gestational age-
based unfractionated heparin dosing to standard dosing of unfractionated heparin for 
pharmacologic thromboprophylaxis of hospitalized antepartum patients.  


 
For our primary objective, we hypothesize that compared to standard dosing, gestational age-
based dosing for VTE prophylaxis is associated with higher rates of elevated aPTT values, a 
surrogate marker of ineligibility for neuraxial anesthesia. For our additional exploratory 
objectives, we hypothesize that there will be no significant difference in achieving goal anti-Xa 
levels (0.2-0.5 IU/mL) between standard dosing and gestational age-based dosing and that 
particular characteristics (e.g., increased eGFR and higher BMI) are associated with elevated 
aPTT values with unfractionated heparin administration.  
 
ACOG Practice Bulletin No.123. Thromboembolism in Pregnancy. Obstet Gynecol 
2011;118:718-729. 
 
 


Friedman AM, D’Alton ME. Venous thromboembolism bundle: Risk assessment and 
prophylaxis for obstetric patients. Semin Perinatol 2016; 40: 87-92. 
 
2.1 
Risk / Benefit Assessment 
Like all medications, unfractionated heparin has the potential to cause side effects. The most 
common side effects are bleeding or bruising and redness and swelling around the puncture site. 
Rare side effects include hypersensitivity to the medication (hives, fever, swelling of throat, 
difficulty breathing) and thrombocytopenia. If significant side effects occur, the medication will 
be discontinued. Unfractionated heparin does not cross the placenta and is considered safe in 
pregnancy without any increased risk of fetal malformations. Subjects would receive 
unfractionated heparin outside of a research context as part of standard hospital protocol for 
pharmacologic thromboprophylaxis. As a result, participation in this study does not pose 
increased risk in exposure to unfractionated heparin.  
Currently, ACOG and NPMS recommend both gestational age-based or standard unfractionated 
heparin dosing to be considered as standard of care for pharmacologic thromboprophylaxis of 
hospitalized antepartum patients. Because standard dosing is lower than gestational age-based 
dosing, there is a theoretical risk that this lower dose may not provide adequate prophylaxis 
against thrombosis/thromboembolism. However, the absolute risk of venous thrombembolism 
development in hospitalized pregnant patients is low (less than 2%) and standard unfractionated 
heparin dosing has demonstrated efficacy and safety in the general, urologic, and orthopedic 
surgery. Higher gestational age-based dosing may lead to restrictions in receipt of neuraxial 
anesthesia. However, we will be monitoring closely with serial aPTTs and alternating dosing in 
response to these results in order to mitigate this risk for subjects randomized to this dosing arm. 
If not within the study, eligible subjects will receive higher gestational age-based dosing per 
current standard hospital protocol, so subjects randomized to gestational age-based dosing will 
not be at increased risk. 
Blood draws are associated with side effects, including temporary discomfort from the needle 
stick, bruising, and rarely, infection and fainting. All antepartum patients who receive 
unfractionated heparin will undergo serial lab draws as part of standard of care at our institution 
to ensure safety of the medication. Therefore, the risks of blood draw are not significantly 
increased by participation within the study. 
Because the subjects will be randomized into a study arm, there are risks associated with 
randomization. The subject will be assigned to a study group by chance (like a coin flip) rather 


than a medical decision made by the researchers. The study group the subject is assigned to 
might not be the group they would prefer to be in. It might also prove to be less effective or have 
more side effects than the other study group, or standard treatments available for the condition.  
Because information will be collected from each subject’s medical record, there is a possibility 
of a breach of confidentiality. However, all precautionary measures will be taken to ensure that 
confidentiality and privacy are maintained, and that data is stored securely. All conversations 
with subjects will occur in a private setting. All data will be de-identified and coded. A code will 
be kept, but it will be kept on a password protected file separate from the data. All clinical data 
will be entered in REDCap, a secure web-based data management system provided by the 
Clinical Translational Science Institute at UCLA that only the research team will have access to. 
Analysis will be carried out utilizing only the study code numbers. Analyzed information will be 
stored on a password-protected computer with encrypted storage media. All informed 
consents/assents will be stored in PI's office, which is only accessible with a key by the study 
team, in a locked cabinet in accordance with local IRB guidelines. 
As for benefits, subjects randomized to the gestational-age based dosing arm may not directly 
benefit from participating in this study. However, information from this study will improve the 
understanding of dosing of unfractionated heparin for pharmacologic VTE prophylaxis. This 
would benefit future pregnant patients. For subjects randomized to the standard dosing arm, there 
is potential that the standard dose demonstrates adequate thromboprophylaxis without an 
increased risk of bleeding or restrictions on neuraxial anesthesia. Subjects randomized to this 
standard dosing arm would receive direct benefit in receiving this dose. 
The risks involved with participation, specifically exposure to unfractionated heparin and blood 
draws, are not significantly higher than antepartum patients that elect to not participate in the 
study because antepartum patients receive gestational age-based dosing of unfractionated heparin 
with serial lab measurements as part of standard of care at our institution. Subjects randomized to 
the standard dosing arm encounter the theoretical risk of the lower dose providing inadequate 
prophylaxis against thrombosis/thromboembolism. However, this absolute risk is low (less than 
2%), and subjects randomized to the standard dosing arm may receive direct benefit from the 
study if the lower dose demonstrate adequate efficacy with an improved safety profile. Overall, 
the risks of participation are limited, some subjects may receive direct benefit, and this study 
would provide valuable information to improve the understanding of dosing of unfractionated 
heparin for pharmacologic VTE prophylaxis. As a result, the risk/benefit ratio is favorable. 
3 STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective is to compare gestational age-based dosing to standard dosing of 
unfractionated heparin for thromboprophylaxis of pregnant patients with prolonged 
hospitalizations and determine its effect on receipt of neuraxial anesthesia and pregnancy 
outcomes.  
3.2 
Secondary Objectives 
The secondary objective of this study is to evaluate pharmacokinetics and pharmacodynamics of 
unfractionated heparin in pregnancy. 


a) Determine the frequency of adjusted unfractionated heparin dosing based on elevated aPTT 
values and assess maternal characteristics associated with elevated aPTT values. 
b) Determine the appropriate dosing of unfractionated heparin for pharmacologic 
thromboprophylaxis of hospitalized antepartum patients (anti-Xa levels within prophylactic goal 
grange, normal aPTT).   
4 STUDY DESIGN 
4.1 
Study Overview 
This is a single center, open-label, non-placebo-controlled, randomized trial of gestational age-
based dosing and standard dosing of unfractionated heparin for pharmacologic 
thromboprophylaxis of antepartum patients hospitalized for at least 72 hours. 46 (23 in arm 1 and 
23 in arm 2) subjects are planned. 
 
Screening data will be reviewed to determine subject eligibility. Subjects who meet all inclusion 
criteria and none of the exclusion criteria will be recruited for the study. Each subject will be 
assigned to receive one of two dosing of unfractionated heparin. Subjects will be assigned to the 
doses in random order.  
The following treatment regimens will be used: 
- 
ARM 1 (Control Arm) 
o Standard dosing: 5,000 units subcutaneous unfractionated heparin every 12 hours 
- 
ARM 2 
o Gestational age-based dosing:  
▪ 1st trimester (< 14 weeks of gestation): 5,000 units subcutaneous 
unfractionated heparin every 12 hours 
▪ 2nd trimester (14-28 weeks of gestation): 7,500 units subcutaneous 
unfractionated heparin every 12 hours 
▪ 3rd trimester (> 28 weeks of gestation): 10,000 units subcutaneous 
unfractionated heparin every 12 hours 
Patients will receive serial lab measurements after 2nd dose, 4th dose, 10th dose, and then weekly 
to monitor. Dosing will be adjusted based on aPTT values (APPENDIX 1).  
 
Total duration of subject participation will be throughout the patient’s inpatient hospitalization 
until they undergo delivery or discharge. Total duration of the study is anticipated to be 
approximately 18 months.  
5 CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
- 
Elevated serum aPTT value above the normal range (> 36.2 seconds). Prophylactic 
dosing of anticoagulation should not cause elevations in coagulation parameters.  
o To be assessed after 2nd dose, 4th dose, and then weekly while receiving 
unfractionated heparin 
o Surrogate marker for whether or not the patient would be eligible for neuraxial 
anesthesia based on guidelines for neuraxial anesthesia in pregnant women 
receiving VTE prophylaxis 


▪ American Society for Regional Anesthesia (ASRA)  
• 5,000 units every 12 hours – normal aPTT value or 4 hours since 
last dose  
• 7,500 – 10,000 units every 12 hours – normal aPTT value and 12 
ours since last dose 
▪ Society of Obstetric Anesthesia and Perinatology 
• 5,000 units every 12 hours – always eligible for neuraxial 
anesthesia 
• 7,500 – 10,000 units every 12 hours – normal aPTT value or 12 
hours since last dose  
5.2 
Secondary Efficacy Endpoints 
- 
Diagnosis of venous thromboembolism (pulmonary embolism and/or deep venous 
thromboembolism) 
- 
Nonreceipt or delay of neuraxial anesthesia due to unfractionated heparin defined as 
inability to receive neuraxial anesthesia due to an elevated aPTT value or because the 
subject received heparin  
- 
Receipt of general anesthesia due to unfractionated heparin  
- 
Delay in timing of delivery due to unfractionated heparin defined as presence of an 
indication to proceed with delivery via cesarean delivery or induction of labor but this 
does not immediately occur due to an elevated aPTT value or because the subject 
received heparin 
- 
Mode of delivery  
- 
Estimated blood loss at time of delivery 
- 
Receipt of blood transfusion  
- 
CBC for hemoglobin and platelet count (to be assessed weekly while receiving 
unfractionated heparin) 
- 
Anti-Xa levels (to be assessed with aPTTs while receiving unfractionated heparin) 
- 
Goal anti-Xa level achieved (0.2-0.5 IU/mL) 
- 
Number of times adjustment in dose made 
- 
Development of side effects from heparin administration (e.g bruising, epistaxis) 
- 
Neonatal outcomes  
o Gestational age at delivery 
o Birthweight 
o 1 minute and 5 minute APGAR scores 
o Cord blood gas values: umbilical artery pH, umbilical artery CO2, umbilical 
artery base excess 
o NICU admission  
o Neonatal death  
6 SUBJECT SELECTION 
6.1 
Study Population 
Subjects that are pregnant and undergoing antepartum admission for at least 72 hours who meet 
the inclusion and exclusion criteria will be eligible for participation in this study.   


6.2 
Inclusion Criteria 
1. Female ≥ 18 years of age at Visit X. 
2. Antepartum admission for at least 72 hours at Ronald Reagan UCLA Medical Center 
3. Speaks English or Spanish 
4. Written informed consent (and assent when applicable) obtained from subject or subject’s 
legal representative and ability for subject to comply with the requirements of the study. 
6.3 
Exclusion Criteria 
1. Active or threatened antenatal bleeding 
2. Risk of imminent delivery (delivery within 12 hours)  
3. Disseminated intravascular coagulation 
4. Thrombocytopenia (platelet count < 100 x 109) 
5. Elevated baseline aPTT (> 36.2 seconds) 
6. Concern for hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome  
7. Congenital bleeding disorders (e.g., hemophilias) 
8. Receiving therapeutic or prophylactic anticoagulation (unfractionated heparin, low 
molecular weight heparin, oral anticoagulants) for alternative indications (e.g., acquired or 
inherited thrombophilia, history of VTE)  
9. History of heparin-induced thrombocytopenia (HIT)  
10. SARS-CoV-2 positive  
11. Cognitive impairment, psychiatric instability, or language barriers that limit their ability to 
provide informed consent  
12. Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the patient or the quality of the data. 
7 CONCURRENT MEDICATIONS 
7.1 
Allowed Medications and Treatments 
Standard therapy provided in pregnancy is allowed except for treatments noted in the exclusion 
criteria described above and as noted in the prohibited medications section below.   
Prohibited Medications and Treatments 
The following medications are prohibited during the study and administration will be considered 
a protocol violation. 
● Low molecular weight heparin 
● Oral anticoagulants 


8 STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
46 eligible patients will be randomly assigned to standard dosing of unfractionated heparin or 
gestational age-based dosing of unfractionated heparin in a 1:1 ratio. They will immediately be 
allocated to their designated arm and this will be documented in their prenatal record. The 
medical team will be notified of the patient’s designated arm and then place the order for 
unfractionated heparin.  
8.2 
Blinding 
Due to the objectives of the study, the identity of dosing will be known to investigators, medical 
providers, and patients. This study is non-blinded.  
8.3 
Formulation of Test and Control Products 
The drug product to be studied is unfractionated heparin, which is a previously standardized 
medication. Formulation will be per UCLA pharmacy.  
8.3.1 
Formulation of Test Product 
The tested product will be two variations in dosing of unfractionated heparin. Formulation and 
dispensing of medication will be per UCLA pharmacy after the appropriate order with assigned 
dosing is placed by the medical team.  
8.3.2 
Formulation of Control Product 
No control product will be provided.  
8.3.3 
Packaging and Labeling 
Not applicable. 
8.4 
Supply of Study Drug at the Site 
Unfractionated heparin will be provided by the UCLA pharmacy.  
8.4.1 
Dosage/Dosage Regimen 
ARM 1: Standard dosing  
- 
Dose: 5,000 units unfractionated heparin subcutaneous injection every 12 hours  
- 
Decrease in dosing will be made for elevated aPTT > 36.2 seconds (APPENDIX 1)  
 
ARM 2: Gestational age-based dosing 
- 
Dose:  
o If less than 14 weeks of gestation - 5,000 units unfractionated heparin 
subcutaneous injection every 12 hours 
o If 14 weeks of gestation to 27 and 6 weeks of gestation – 7,500 units 
unfractionated heparin subcutaneous injection every 12 hours 
o If greater than or equal to 28 weeks of gestation – 10,000 units unfractionated 
heparin subcutaneous injection every 12 hours  


- 
Decrease in dosing will be made for elevated aPTT > 36.2 seconds (APPENDIX 1) 
8.4.2 
Dispensing 
The pharmacist will dispense the drug. 
8.4.3 
Administration Instructions  
The assigned inpatient nurse caring for the patient will administer the drug.  
8.5 
Supply of Study Drug at the Site 
Not applicable since this is not a study drug. 
8.5.1 
Storage 
Unfractionated heparin will be stored in the pharmacy per UCLA pharmacy protocol.  
8.6 
Study Drug Accountability 
Not applicable since this is not a study drug. 
8.7 
Measures of Treatment Compliance 
Treatment compliance will be ensured through study staff’s evaluation of the patient’s 
medication administration record (MAR) in the medical chart. This provides information on dose 
provided and time of administration.  
9 STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures and adjustments in dosing of 
medications to be performed for the duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and dated 
by the subject or subject’s legal representative. If appropriate, assent must also be obtained prior 
to conducting any study-related activities. 
9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at screening. Dose, 
route, unit frequency of administration, and indication for administration and dates of medication 
will be captured. 
9.1.2 
Demographics  
Demographic information (date of birth, gender, race) will be recorded at screening. 
9.1.3 
Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory history, 
and information regarding underlying diseases will be recorded at screening. 


9.1.4 
Physical Examination 
A complete physical examination will be performed by the medical team, which consists of a 
physician at UCLA Medical Center, on admission to the hospital. This physical exam will be 
documented in the medical chart. The medical team (MD, RN) will perform physical exams 
daily per hospital protocol and monitor for development of side effects (e.g., bruising, rash, 
epistaxis). New abnormal physical exam findings must be documented and will be followed by a 
physician once reported.  
9.1.5 
Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed after resting for 
5 minutes at least once daily as part of the patient’s hospitalization.  
9.1.6 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), outcome, treatment and relation to study drug will be 
recorded on the case report form (CRF). 
9.2 
Clinical Laboratory Measurements 
9.2.1 
Hematology 
Blood will be obtained and sent to to the clinical hematology lab for a complete blood count 
(hemoglobin, hematocrit, red blood cell count, white blood cell count, white blood cell 
differential, and platelet count), activated partial thromboplastin time (aPTT), and anti-Xa levels. 
9.2.2 
Blood Chemistry Profile 
Blood will be obtained and sent to each clinical chemistry lab for determination of creatinine. 
10 EVALUATIONS BY VISIT 
REFER TO APPENDIX 2 
10.1 
Visit 1: Day 1  
1. 
Review the study with the subject (subject’s legal representative) and obtain written 
informed consent and HIPAA authorization and assent, if appropriate. 
2. 
Assign the subject a unique screening number. 
3. 
Record demographics data. 
4. 
Record medical and surgical history 
5. 
Record concomitant medications. 
6. 
Collect blood for clinical laboratory tests (CBC, aPTT, anti-Xa, serum creatinine). 
7. 
Randomize subject 
8. 
Order unfractionated heparin dosing that subject is randomized to (first dose ordered for 
21:00 PM the day patient is randomized)  


10.2 
Visit 2: Day 2  
1. 
Record any Adverse Experiences  
2. 
Record times when patient received unfractionated heparin or noncompliance to 
medication 
3. 
Collect blood for aPTT and anti-Xa 6 hours after second dose of heparin (~15:00 PM on 
day 2)  
4. 
Follow-up aPTT  
a. If < 36.2 seconds, continue current dose of heparin 
b. If > 36.2 seconds, adjust heparin dose and repeat aPTT, anti-Xa, and serum creatinine 
per protocol (APPENDIX 1)  
10.3 
Visit 3: Day 3 
1. 
Record any Adverse Experiences  
2. 
Record times when patient received unfractionated heparin or had noncompliance to 
medication 
3. 
Collect aPTT and anti-Xa 2 hours after fourth dose of heparin (~11:00 AM on day 3) 
4. 
Collect aPTT and anti-Xa 6 hours after fourth dose of heparin (~15:00 PM on day 3) 
5. 
Follow-up aPTT 
a. If < 36.2 seconds, continue current dose of heparin 
b. If > 36.2 seconds, adjust heparin dose and repeat aPTT and anti-Xa per protocol 
(APPENDIX 1)  
10.4 
Visit 4: Day 6  
1. 
Record any Adverse Experiences or side effects 
2. 
Record times when patient received unfractionated heparin or had noncompliance to 
medication 
3. 
Collect CBC, aPTT, and anti-Xa 6 hours after tenth dose of heparin (~15:00 PM on day 6) 
4. 
Follow up aPTT 
a. If < 36.2 seconds, continue current dose of heparin 
b. If > 36.2 seconds, adjust heparin dose and repeat aPTT and anti-Xa per protocol 
(APPENDIX 1)  
10.5 
Weekly Visits (Day 13, 20, 27, 34+ until delivery or discharge from hospital)   
1. 
Record any Adverse Experiences or side effects 
2. 
Record times when patient received unfractionated heparin or had noncompliance to 
medication 
3. 
Collect CBC, aPTT, and anti-Xa 6 hours after AM dose of heparin (~15:00 PM) 


4. 
Follow up aPTT 
a. If < 36.2 seconds, continue current dose of heparin 
b. If > 36.2 seconds, hold or decrease heparin dose and repeat aPTT and anti-Xa per 
protocol (APPENDIX 1) 
10.6 
Early Withdrawal Visit 
1. 
Record any Adverse Experiences or side effects 
2. 
Record times when patient received unfractionated heparin or had noncompliance to 
medication 
3. 
Collect aPTT and anti-Xa 6 hours after AM dose of heparin  
11 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be 
written describing all analyses that will be performed.  The SAP will contain any modifications 
to the analysis plan described below.   
11.1 
Data Sets Analyzed 
All patients randomized into the study that received two doses of unfractionated heparin and had 
at least one aPTT measurement available for review will be included within the analysis.  
11.2 
Demographic and Baseline Characteristics 
The following demographic variables will be collected at screening: age, height and weight, 
body mass index, race, ethnicity. The following baseline characteristics will be collected at 
screening: gestational age at randomization, gravida, parity, maternal comorbidities. 
11.3 
Analysis of Primary Endpoint 
Analysis of the primary endpoint of whether or not there was an elevation in aPTT in each 
dosing group will be performed with a Chi-squared test. Comparison will be considered 
statistically significant at a p-value of < 0.05.  
11.4 
Analysis of Secondary Endpoints 
Comparison of maternal demographics, baseline characteristics, additional maternal outcomes, 
and neonatal outcomes between the two groups will be analyzed using Student’s t-test for 
parametric data, Wilcoxon signed-rank test for nonparametric data, and Chi-squared or Fisher’s 
exact test for comparison of proportions. Descriptive statistics will be performed to summarize 
which dose resulted in a normal aPTT value and anti-Xa within goal range. Multivariate logistic 
regression analysis will be performed to determine which factors were associated with an 
elevated aPTT value. Statistical significance will be set at a p-value of < 0.05 or 95% confidence 
interval not overlapping.  
11.5 
Sample Size and Randomization 
Based on an informal/pilot review of antepartum admissions at our institution receiving 
gestational age-based dosing of unfractionated heparin, 40% of patients and an elevated aPTT 


value. Assuming 40% of patients receiving gestational age-based dosing and 3% receiving 
standard dosing had elevated serum aPTT values, a sample size of 18 women in each dosing 
group would have 80% power (alpha = 0.05) to demonstrate a significant difference in our 
primary outcome of evaluating the proportion of women with elevated aPTT values after heparin 
administration. We increased the sample size by 25% to account for post-randomization drop-out 
or lab sampling errors. We plan to recruit 46 patients.  
12 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
12.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with the treatment.  An AE is therefore any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the administration 
of an investigational product, whether or not related to that investigational product.  An 
unexpected AE is one of a type not identified in nature, severity, or frequency in the current 
Investigator’s Brochure or of greater severity or frequency than expected based on the 
information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs during 
each subject visit and record the information in the site’s source documents.  Adverse events will 
be recorded in the patient CRF.  Adverse events will be described by duration (start and stop 
dates and times), severity, outcome, treatment and relation to study drug, or if unrelated, the 
cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 3.0 should be used to assess and grade AE severity, including laboratory abnormalities 
judged to be clinically significant. The modified criteria can be found in the study manual.  If the 
experience is not covered in the modified criteria, the guidelines shown in Table 1 below should 
be used to grade severity.  It should be pointed out that the term “severe” is a measure of 
intensity and that a severe AE is not necessarily serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
AE Relationship to Study Drug 


The relationship of an AE to the study drug should be assessed using the following the guidelines 
in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
12.2 
Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
● death 
● a life-threatening adverse experience 
● inpatient hospitalization or prolongation of existing hospitalization 
● a persistent or significant disability/incapacity 
● a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed.  
 
12.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per UCLA 
OHRPP Guidelines.  The collection period for all SAEs will begin after informed consent is 
obtained and end after procedures for the final study visit have been completed. 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report SAEs 
to the IRB/IEC.   
12.3 
Medical Monitoring 
Thalia Mok should be contacted directly at these numbers to report medical concerns or 
questions regarding safety. 


Phone: (310) 210-2246 
Pager: x31460 
13 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
13.1 
Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject or the investigator 
feels that it is not in the subject’s best interest to continue.  The following is a list of possible 
reasons for study treatment discontinuation:  
● Subject withdrawal of consent (or assent) 
● Subject is not compliant with study procedures 
● Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study treatment 
● Protocol violation requiring discontinuation of study treatment 
● Lost to follow-up 
● Sponsor request for early termination of study 
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed 
and treated by the Investigator until the abnormal parameter or symptom has resolved or 
stabilized.   
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals. The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents Refer to Section 10 for early termination procedures. 
13.2 
Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject or the investigator feels 
that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents. Refer to Section 10 for early termination procedures.   
13.3 
Replacement of Subjects 
Subjects who withdraw from the study treatment will not be replaced.   
14 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject or investigator fails to adhere to significant protocol 
requirements affecting the inclusion, exclusion, subject safety and primary endpoint criteria.  
Protocol violations for this study include, but are not limited to, the following: 


● Failure to meet inclusion/exclusion criteria 
● Use of a prohibited concomitant medication 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The principal investigators will determine if a protocol violation will result in 
withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a Sponsor 
representative and the Investigator. A copy of the form will be filed in the site’s regulatory 
binder and in the Sponsor’s files. 
15 DATA COLLECTION, RETENTION AND MONITORING 
15.1 
Data Collection Instruments 
All clinical data will be entered by the Investigator in REDCap, a secure web-based data 
management system provided by the Cinical Translational Science Institute at UCLA that only 
the research team has access to. Each subject will also have a protocol-specific Case Report 
Form (eCRF) where the investigator will report the following information: 
- 
Date of randomization 
- 
Randomization to ARM 1 (standard dosing) or ARM 2 (gestational-age based dosing) 
- 
Dosing of unfractionated heparin received 
- 
Number of times unfractionated heparin dose was changed 
- 
Side effects 
- 
Adverse events  
Subjects will not be identified by name in the study database or on any study documents to be 
collected by the Sponsor (or designee), but will be identified by a subject number and initials. If 
a correction is made on a CRF, the investigator will line through the incorrect data, write in the 
correct data and initial and date the change. 
The investigator is responsible for all information collected on subjects enrolled in this study.  
All data collected during the course of this must be reviewed and verified for completeness and 
accuracy by the investigator. 
15.2 
Data Management Procedures 
The data will be entered in REDCap, a secure web-based data management system provided by 
the Clinical Translational Science Institute at UCLA. Only the research team will have access to 
the data and be responsible for data processing, in accordance with procedural documentations. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 
15.3 
Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with any 
updates or changes to the database.   


15.4 
Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized representatives 
of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) inspectors upon 
request.  A file for each subject must be maintained that includes the signed Informed Consent, 
HIPAA Authorization and Assent Form and copies of all source documentation related to that 
subject.  The Investigator must ensure the reliability and availability of source documents from 
which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File 
Notebook, etc.) must be kept secured for a period of two years following marketing of the 
investigational product or for two years after centers have been notified that the IND has been 
discontinued.  There may be other circumstances for which the Sponsor is required to maintain 
study records and, therefore, the Sponsor should be contacted prior to removing study records for 
any reason. 
15.5 
Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor according to the U.S. CFR 
Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).    By signing this protocol, the 
Investigator grants permission to the Sponsor (or designee), and appropriate regulatory authorities 
to conduct on-site monitoring and/or auditing of all appropriate study documentation. 
15.6 
Subject Confidentiality 
In order to maintain subject confidentiality, only a subject number will identify all study subjects 
on CRFs and other documentation.  Additional subject confidentiality issues (if applicable) are 
covered in the Clinical Study Agreement. 
16 DATA AND SAFETY MONITORING PLAN 
SEE APPENDIX 3 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records 
will be identified by a coded number and initials only.  All study records will be kept in a locked 
file cabinet and code sheets linking a patient’s name to a patient identification number will be 
stored separately in another locked file cabinet.  Clinical information will not be released without 
written permission of the subject, except as necessary for monitoring by the FDA.  The 
Investigator must also comply with all applicable privacy regulations (e.g., Health Insurance 
Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
17.1 
Protocol Amendments 
Any amendment to the protocol will be written by the principal investigators.  Protocol 
amendments cannot be implemented without prior written IRB/IEC approval except as necessary 
to eliminate immediate safety hazards to patients.  A protocol amendment intended to eliminate 


an apparent immediate hazard to patients may be implemented immediately, provided the IRBs 
are notified within five working days. 
17.2 
Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of causality 
will be reported to the IRB/IEC in accordance with the standard operating procedures and 
policies of the IRB/IEC, and the Investigator will keep the IRB/IEC informed as to the progress 
of the study.  The Investigator will obtain assurance of IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning patient 
recruitment, payment or compensation procedures, or other pertinent information) will be 
submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the study protocol 
and the informed consent form will be in the possession of the Investigator before the study is 
initiated.  This approval must refer to the study by exact protocol title and number and should 
identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB/IEC approval except when necessary to eliminate immediate hazards to the patients 
or when the change(s) involves only logistical or administrative aspects of the study.  Such 
modifications will be submitted to the IRB/IEC and written verification that the modification 
was submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect 
adversely the safety of the patients of the conduct of the study; an annual update and/or request 
for re-approval; and when the study has been completed. 
17.3 
Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US 
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, 
and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, 
if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization and 
provide the documents to the Sponsor or designee for approval prior to submission to the 
IRB/IEC.  The consent form generated by the Investigator must be acceptable to the Sponsor and 
be approved by the IRB/IEC.  The written consent document will embody the elements of 
informed consent as described in the International Conference on Harmonisation and will also 
comply with local regulations. The Investigator will send an IRB/IEC-approved copy of the 
Informed Consent Form to the Sponsor (or designee) for the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written form and 
subjects (or their legal representatives) must be given ample opportunity to inquire about details 
of the study.  If appropriate and required by the local IRB/IEC, assent from the subject will also 
be obtained.  If a subject is unable to sign the informed consent form (ICF) and the HIPAA 


authorization, a legal representative may sign for the subject.   A copy of the signed consent form 
(and assent) will be given to the subject or legal representative of the subject and the original will 
be maintained with the subject’s records. 
17.4 
Publications  
The preparation and submittal for publication of manuscripts containing the study results shall be 
in accordance with a process determined by mutual written agreement among the study Sponsor 
and participating institutions.  The publication or presentation of any study results shall comply 
with all applicable privacy laws, including, but not limited to, the Health Insurance Portability 
and Accountability Act of 1996.  
17.5 
Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after notifying 
the Sponsor (or designee), except when to protect the safety, rights or welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity 
and all unanticipated problems involving risks to subjects or others (to include amendments 
and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
 
 


References 
1. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF. WHO analysis of causes of 
maternal death: a systematic review. Lancet. 2006; 367:1066-1074. 
2. Abdul Sultan A, West J, Tata LJ, Fleming KM, Nelson-Piercy C, Grainge MJ. Risk of first 
venous thromboembolism in pregnant women in hospital: population based cohort study from 
England. BMJ 2013;347:f6099.  
3. Friedman AM, Ananth CV. Obstetrical venous thromboembolism: epidemiology and 
strategies for prophylaxis. Semin Perinatol 2016;40:81-86.  
4. Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, 
thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of 
thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice 
Guidelines. Chest 2012;141(suppl):e691S-736S.  
5. Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, Cook DJ, Balekian AA, Klein 
RC, Le H, Schulman S, Murad MH. Prevention of VTE in nonsurgical patients: antithrombotic 
therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-
Based Clinical Practice Guidelines. Chest 2012;141(suppl):e195-226S.  
6. Thromboembolism in pregnancy. Practice Bulletin No.123. American College of Obstetricians 
and Gynecologists. Obstet Gynecol 2011;118:718-729. 
7. The Royal College of Obstetricians and Gynaecologists. Thrombosis and embolism during 
pregnancy and the puerperium, reducing the risk. Green-top guidelines no. 37a. London (United 
Kingdom): Royal College of Obstetricians and Gynaecologists; 2015. 
8. Cantwell R, Clutton-Brock T, Cooper G, Dawson A, Drife J, Garrod D, Harper A, Hulbert D, 
Lucas S, McClure J, Millward-Sadler H, Neilson J, Nelson-Piercy C, Norman J, O’Herlihy C, 
Oates M, Shakespeare J, de Swiet M, Williamsn C, Beale V, Knight M, Lennox C, Miller A, 
Parmar D, Rogers J, Springett A. Saving Mothers’ Lives: Reviewing maternal deaths to make 
motherhood safer: 2006-2008. The Eighth Report of the Confidential Enquiries into Maternal 
Deaths in the United Kingdom. BJOG. 2011;118 suppl 1:1-203. 
9. D’Alton ME, Friedman AM, Smiley RM, Montgomery DM, Paidas MJ, D’Oria RMA, Frost J, 
Hameed A, Karsnitz D, Levy BS, Clark S. National Partnership for Maternal Safety: Consensus 
Bundle on Venous Thromboembolism. Obstet Gyneol 2016; 128: 688-698. 
10. Flessa HC, Kapstrom AB, Glueck HI, Will JJ. Placental transport of heparin. Am J Obstet 
Gynecol 19665; 93: 570-573.  
11. Harenberg J, Schneider D, Heilmann L, Wolf H. Lack of anti-factor Xa activity in umbilical 
cord vein samples after subcutaneous administration of heparin or low molecular mass heparin in 
pregnant women. Haemostasis 1993; 23: 314-320. 
12. Greer IA, Nelson-Peircy C. Low-molecular-weight heparins for thromboprophylaxis and 
treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. 
Blood 2005; 106: 401-407. 
13. Chunilal SD, Young E, Johnston MA, Robertson C, Naguit I, Stevens P, Galashan D, 
Oskamp ML, Brennan B, Ginsberg JS. The APTT Response of Pregnant Plasma to 
Unfractionated Heparin. Thromb Haemost 2002; 87: 92-97. 
14. Brancazio LR, Roperti KA, Stierer R, Laifer SA. Pharmacokinetics and pharmacodynamics 
of subcutaneous heparin during early third trimester of pregnancy. Am J Obstet Gynecol 1995; 
173(4): 1240-1245.  
15. Barbour LA, Smith JM, Marlar RA. Heparin levels to guide thromboembolism prophylaxis 
during pregnancy. Am J Obstet Gynecol 1995; 173(6): 1869-1873. 


16. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and 
venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results 
of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med 1988; 318(8): 
1162-1173. 
17. Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, Samama CM. 
Prevention of VTE in Nonorthopedic Surgical Patients. Antithrombotic Therapy and Prevention 
of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice 
Guidelines. Chest 2012; 141(2): 227-277. 
18. Friedman AM, D’Alton ME. Venous thromboembolism bundle: Risk assessment and 
prophylaxis for obstetric patients. Semin Perinatol 2016; 40: 87-92. 
19. Horlocker TT, Vandermeuelen E, Kopp SL, Gogarten W, Leffer LR, Benzon HT. Regional 
Anesthesia in the Patient Receiving Antithrombotic or Thrombolytic Therapy. American Society 
of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Fourth Edition). Reg 
Anesth Pain Med 2018; 43(3): 263-309. 
20. Leffert L, Landau R. Integrating the New Thromboprophylaxis Guidelines Into Obstetric 
Anesthesia Practice. Anesth Analg 2016; 123(4): 809-811. 
21. American Society of Regional Anesthesia and Pain Medicine. ASRA Coags (Version 1.5) 
[Mobile application software]. Available at https://itunes.apple.com/us/app/asra-
coags/id858796572?mt58. Retrieved March 11, 2020.  
22. Leffert L, Butwick A, Carvalho B, Arendt K, Bates S, Friedman A, Horlocker T, Houle T, 
Landau R. SOAP VTE Taskforce. The Society for Obstetric Anesthesia and Perinatology 
Consensus Statement on the Anesthetic Management of Pregnant and Postpartum Women 
Receiving Thromboprophylaxis of Higher Dose Anticoagulants. Anesth Analg 2018; 26(3): 928-
944.  
 


APPENDIX 1.  Study Dosing Protocol  
 
Antepartum patient 
hospitalized for > 72 hours
Exclusion criteria:
- Active or threatened antenatal bleeding
- Risk of imminent delivery
- Disseminated intravascular coagulation
- Thrombocytopenia (platelet count < 100 x 109)
- Evolving HELLP syndrome 
- Elevated baseline aPTT (> 36.2 seconds)
- Congenital bleeding disorders (hemophilia) 
- Receiving therapeutic or prophylactic anticoagulation 
for alternative indication (e.g., acquired or inherited 
thrombophilia, hx of VTE)
- History of HIT 
- SARS-CoV-2 positive
- Inability to provide consent 
ARM 1
ARM 2
Gestational Age-Based Heparin Dosing
1st trim (< 14 wks): 5,000 units SC q12 hrs
2nd trim (14-28 wks): 7,500 units SC q12 hrs
3rd trim (> 28 wks): 10,000 units SC q12 hrs
Serial aPTT + anti-Xa:
- 6 hours after 2nd dose
- 2 hours after 4th dose 
- 6 hours after 4th dose
- 6 hours after 10th dose
- Every week (6 hours after dose)
MD team records side effects 
after 10th dose à weekly
aPTT > 36.2
Decrease to 2,500 units q12 hrs
Repeat aPTT, anti-Xa, Cr 6 hours after new dose
aPTT < 36.2
aPTT > 36.2
Hold heparin
Serial aPTT +  anti-Xa:
- 6 hours after 2nd dose
- 2 hours after 4th dose 
- 6 hours after 4th dose
- 6 hours after 10th dose
- Every week (6 hours after dose)
MD team records side effects 
after 10th dose à weekly
aPTT > 36.2
Decrease to 7,500 units q12 hrs
Repeat aPTT, anti-Xa, creatinine 6 hours after new dose
aPTT < 36.2
aPTT > 36.2
Hold next dose
Serial aPTT + anti-Xa:
- 6 hours after 2nd dose
- 2 hours after 4th dose
- 6 hours after 4th dose
- 6 hours after 10th dose
- Every week (6 hours after dose)
MD team records side effects 
after 10th dose à weekly
Decrease to 5,000 units q12 hrs
Repeat aPTT, anti-Xa, Cr 6 hours after new dose
aPTT < 36.2
aPTT > 36.2
Hold next dose
Serial aPTT + anti-Xa:
- 6 hours after 2nd dose
- 2 hours after 4th dose 
- 6 hours after 4th dose
- 6 hours after 10th dose
-
Every week (6 hours after dose)
MD team records side effects 
after 10th dose à weekly
Decrease to 2,500 units q12 hrs
Repeat aPTT, anti-Xa, Cr 6 hours after new dose
aPTT < 36.2
aPTT > 36.2
Hold heparin
Serial aPTT + anti-Xa:
- 6 hours after 2nd dose
- 2 hours after 4th dose 
- 6 hours after 4th dose
- 6 hours after 10th dose
- Every week (6 hours after dose)
MD team records side effects 
after 10th dose à weekly
Antepartum HEPARIN Dosing RCT Protocol
Baseline labs:
CBC, aPTT, anti-Xa, creatinine
Standard Heparin Dosing
5,000 units SC q12 hrs
Indications for Holding Heparin: 
- Risk of imminent delivery
- Active or threatened antenatal bleeding
- Evolving HELLP syndrome
- Thrombocytopenia (platelet count < 100 x 109)
- Severe anemia (Hb < 7)
- Concern for HIT 
Repeat aPTT + anti-Xa every
12 hours until aPTT < 36.2
Repeat aPTT + anti-Xa every
12 hours until aPTT < 36.2
Serial aPTT + anti-Xa:
- 6 hours after 2nd dose
- 2 hours after 4th dose 
- 6 hours after 4th dose
- 6 hours after 10th dose
- Every week (6 hours after dose)
MD team records side effects 
after 10th dose à weekly


APPENDIX 2. Schedule of Events 
ARM 1: Standard dose of unfractionated heparin 
 
VISIT 
(Day 1 – 
Baseline) 
VISIT 2 
(Day 2) 
VISIT 3 
(Day 3) 
VISIT 4 
(Day 6) 
WEEKLY VISITS 
(Day 13, 20, 27+ until 
delivery or discharge) 
Informed Consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Complete Physical Exam 
X 
 
 
 
 
Abbreviated Physical Exam 
 
X 
X 
X 
X 
Height  
X 
 
 
 
 
Weight  
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
Concomitant medications 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Unfractionated heparin given 
X 
X 
X 
X 
X 
CBC 
X 
 
 
X 
X 
Trough aPTT 
X 
X 
6 hours after 
heparin at 
~15:00 PM 
X 
6 hours after 
heparin at 
~15:00 PM 
X 
6 hours after 
heparin at 
~15:00 PM 
X 
6 hours after heparin  
at ~15:00 PM 
Trough Anti-Xa  
X 
X 
6 hours after 
heparin at 
~15:00 PM 
X 
6 hours after 
heparin at 
~15:00 PM 
X 
6 hours after 
heparin at 
~15:00 PM 
X 
6 hours after heparin  
at ~15:00 PM 
Serum creatinine 
X 
 
 
 
 
Peak aPTT 
 
 
X 
2 hours after 
heparin at 
~11:00 AM 
 
 
Peak Anti-Xa 
 
 
X 
2 hours after 
heparin at 
~11:00 AM 
 
 
Adverse Experiences 
 
X 
X 
X 
X 
Follow-up trough aPTT (adjust or 
keep dose per APPENDIX 1)  
 
X 
X 
X 
X 
Assess side effects  
 
 
 
X 
X 
 


ARM 2 : Gestational-age based dose of unfractionated heparin 
 
VISIT 
(Day 1 – 
Baseline) 
VISIT 2 
(Day 2) 
VISIT 3 
(Day 3) 
VISIT 4 
(Day 6) 
WEEKLY VISITS 
(Day 13, 20, 27+ until 
delivery or discharge) 
Informed Consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Complete Physical Exam 
X 
 
 
 
 
Abbreviated Physical Exam 
 
X 
X 
X 
X 
Height  
X 
 
 
 
 
Weight  
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
Concomitant medications 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Unfractionated heparin given 
X 
X 
X 
X 
X 
CBC 
X 
 
 
X 
X 
Trough aPTT 
X 
X 
6 hours after 
heparin at 
~15:00 PM 
X 
6 hours after 
heparin at 
~15:00 PM 
X 
6 hours after 
heparin at 
~15:00 PM 
X 
6 hours after heparin  
at ~15:00 PM 
Trough Anti-Xa  
X 
X 
6 hours after 
heparin at 
~15:00 PM 
X 
6 hours after 
heparin at 
~15:00 PM 
X 
6 hours after 
heparin at 
~15:00 PM 
X 
6 hours after heparin  
at ~15:00 PM 
Serum creatinine 
X 
 
 
 
 
Peak aPTT 
 
 
X 
2 hours after 
heparin at 
~11:00 AM 
 
 
Peak Anti-Xa 
 
 
X 
2 hours after 
heparin at 
~11:00 AM 
 
 
Adverse Experiences 
 
X 
X 
X 
X 
Follow-up trough aPTT (adjust or 
keep dose per APPENDIX 1)  
 
X 
X 
X 
X 
Assess side effects  
 
 
 
X 
X 
 
   
 
 


APPENDIX 3. Data and Safety Monitoring Plan  
Study Title: Randomized Control Trial of Unfractionated Heparin Dosing for 
Thromboprophylaxis of Hospitalized Antepartum Patients 
 
Principal Investigator: Thalia Mok, MD and Rashmi Rao, MD  
 
I. 
Study Overview 
A. Purpose of the study 
Venous thromboembolism (VTE) is one of the leading causes of maternal 
morbidity and mortality, and antepartum hospitalizations place pregnant patients 
at an even higher risk of developing thromboembolism. As a result, there is an 
increased emphasis on administering pharmacologic thromboprophylaxis for 
antepartum patients with prolonged hospitalizations.  
 
Previously, standard dosing of unfractionated heparin was widely adopted for 
thromboprophylaxis in the pregnant population. However, due to a suspected 
altered metabolism of unfractionated heparin in pregnancy resulting in a decrease 
response, the American College of Obstetricians and Gynecologists (ACOG) and 
National Partnership for Maternal Safety (NPMS) currently recommends 
considering gestational age based dosing for unfractionated heparin for 
thromboprophylaxis in pregnancy with standard dosing as an alternative option. 
The data supporting altered dosing is very limited. In addition, increased dosing 
of heparin may result in challenges in anesthetic management, potentially limiting 
the receipt of neuraxial anesthesia resulting in increased need for general 
anesthesia associated with both increased maternal and fetal risks. The potential 
effects of higher prophylactic unfractionated heparin dosing in pregnant patients 
need to be further explored before being widely adopted for inpatient antepartum 
thromboprophylaxis. We propose this study to provide a direct comparison of 
gestational age based unfractionated heparin dosing to standard dosing of 
unfractionated heparin for pharmacologic thromboprophylaxis of hospitalized 
antepartum patients. 
 
B. Adherence statement 
The Data and Safety Monitoring Plan (SMP) outlined below will adhere to the 
protocol approved by the University of California, Los Angeles IRB. 
 
II. 
Adverse events 
A. Adverse event assessment 
The risks that may occur as part of participation in this study are detailed in 
section 2.1 of the study protocol. They include side effects from unfractionated 
heparin, discomfort of blood draws, and limitations in receipt of neuraxial 
anesthesia if resulting activated partial thromboplastin time (aPTT) is above the 
normal range. In order to mitigate risks to subject participants, the study protocol 
closely monitors lab values (aPTT and CBC) and provides subsequent decreases 
in dosing of unfractionated heparin. Because this study only includes hospitalized 
patients, subjects will be continuously assessed for side effects of unfractionated 


heparin and adverse events by the medical team caring for her during the 
hospitalization. In addition, a formal assessment of side effects and adverse events 
will be performed by the investigator on weekly, while the subject is enrolled in 
the study.  
 
B. Adverse event reporting 
Every adverse event that is reported to the principal investigator or research team 
by the subject or medical staff caring for the subject and meets criteria will be 
documented. An adverse event report will be generated for each event and the 
report will include a description of the event, when it was reported, by whom it 
was reported, along with any official chart records or documentation to 
corroborate the event. The report will be provided to the IRB.  
 
III. 
Safety Review Plan and Monitoring 
A. Justification of sample size 
Based on an informal/pilot review of antepartum admissions at our institution 
receiving gestational age-based dosing of unfractionated heparin, 40% of patients 
and an elevated aPTT value. Assuming 40% of patients receiving gestational age- 
based dosing and 3% receiving standard dosing had elevated serum aPTT values, 
a sample size of 18 women in each dosing group would have 80% power (alpha = 
0.05) to demonstrate a significant difference in our primary outcome of evaluating 
the proportion of women with elevated aPTT values after heparin administration. 
We increased the sample size by 25% to account for post-randomization drop-out 
or lab sampling errors. We plan to recruit 46 patients with 23 patients in each arm.  
 
B. Safety and study progress reviews 
Study progress and safety will be reviewed monthly and more frequently if 
needed by the principle investigator. Review of subject accrual and compliance 
with inclusion/exclusion criteria will be performed to ensure that there are 
sufficient number of participants being enrolled and that they meet eligibility 
criteria. Adherence to treatment protocol and subject retention will be reviewed. 
Adverse events and side effects will also be reviewed by the principal investigator 
and reported per above. An interim analysis will be performed when 50% of the 
target sample size (23 subjects) have completed the study. A report will then be 
provided and contain a list and summary of adverse events, summary of 
recruitment and retention and reason for dropouts, and whether or not the study is 
on track to be completed and accomplish the stated aims.  
 
C. Stopping rules 
This study will be stopped prior to its completion if: 
1. Gestational age-based dosing is associated with a significantly higher 
rate (defined as 50% of the study arm) of administration of general 
anesthesia despite dosing adjustments based on aPTT levels.  
2. National guidelines from ACOG change during the trial and state that 
gestational age-based dosing should not be given for our study 
population.  


3. Maternal or neonatal death occur secondarily to administration of 
unfractionated heparin. 
 
IV. 
Informed Consent 
Informed consent will be obtained from each subject before enrollment and per local 
institutional review board guidelines. Consent will be obtained in an ethical manner. 
The process of consenting will be obtained in the subject’s primary language. 
Subjects will be provided with written material and will be given ample time to 
review the material and ask questions.  
 
V. 
Data Quality and Management 
Data on treatment protocol and lab values will be evaluated at least weekly by the 
research team and entered into the REDCap database, which is a secure web-based 
data management system provided by the Clinical Translational Science Institute at 
UCLA. The principal investigator will review all data collection forms for data 
completeness and accuracy. The collected data will be verified based on original 
source documents available in the electronic medical records. Only the research team 
will have access to the database. 
 
VI. 
Confidentiality  
All precautionary measures will be taken to ensure that confidentiality and privacy is 
maintained. All conversations with subjects and consents will be performed in a 
private setting. All data will be stored securely and only accessible to the research 
staff. Only a subject ID number will be associated with data to maintain subject 
confidentiality. A code sheet linking subject information to subject ID will be 
maintained but kept on a password protected computer and in a password protected 
file; this will only be accessible to the principle investigators.  
 
 
 
 
 
 

ICF_006.pdf: 
Title of Study: Heparin Prophylaxis Dosing for Antepartum Hospitalizations (HEPDOSE) 
 
NCT Number: NCT04635839 
 
Document Date: October 19, 2021 
 
Document: Informed Consent Form  
 
 


UNIVERSITY OF CALIFORNIA LOS ANGELES 
CONSENT TO PARTICIPATE IN RESEARCH 
 
Study Title: Randomized Control Trial of Unfractionated Heparin Dosing for 
Thromboprophylaxis of Hospitalized Antepartum Patients 
 
INTRODUCTION 
Rashmi Rao, M.D., Thalia Wong, M.D., and associates from the Department of Obstetrics and 
Gynecology at the University of California, Los Angeles are conducting a research study.  
 
The study doctor and/or study staff will explain this study to you. Research studies are 
voluntary and include only people who choose to take part. Please take your time about 
deciding whether to participate in this study. Before deciding: 
 
• 
You can discuss this study with friends and family. 
• 
You can discuss this study with your health care doctor or request a second opinion. 
• 
If you have any questions, you can ask the study doctor or study staff for more 
information before deciding to participate.  
 
KEY INFORMATION: 
The following is a short summary of this study to help you decide whether or not to be a part of 
this study. More detailed information is listed later on in this form. 
 
Why am I being invited to take part in a research study? 
We invite you to take part in this research study because you are pregnant and will be admitted 
to the hospital for at least 72 hours.  
 
What should I know about a research study? 
• 
Someone will explain this research study to you. 
• 
Whether or not you take part is up to you. 
• 
You can choose not to take part. 
• 
You can agree to take part and later change your mind. 
• 
Your decision will not be held against you. 
• 
You can ask all the questions you want before you decide. 
• 
You can discuss this study with friends and family. 
• 
You can also discuss it with your health care doctor request a second opinion. 
 
Why is this research being done? 
Pregnant patients who are hospitalized for a prolonged period of time are at an increased risk of 
developing a venous thromboembolism (e.g., a clot in your legs or lung). Because of this 
increased risk, it is recommended to place pregnant patients who are hospitalized for at least 72 
hours on prophylactic anticoagulation (e.g., low dose preventive blood thinner) with 
unfractionated heparin (e.g., medication to slow the formation of blood clots)  to prevent the 
development of clots. Not enough research has been done to determine the best dosing for 
unfractionated heparin in pregnancy.  
 
This study is being conducted to investigate the safety and efficacy of two doses of 
unfractionated heparin that are currently recommended for prophylactic anticoagulation in 
pregnancy: 
Protocol ID:IRB#20-001799    UCLA IRB Approved   Approval Date: 10/19/2021   Through: 10/12/2022   Committee: Medical IRB 1


1. Standard dose of unfractionated heparin outside of pregnancy  
2. Gestational age-based dose of unfractionated heparin (dose of medication depends on 
the trimester of pregnancy you are in and is higher if you are further along in pregnancy) 
 
Both of these doses are considered “standard of care” or acceptable ways to provide 
prophylactic anticoagulation in pregnancy. It is thought that changes to your body during 
pregnancy, including increase in blood volume, greater excretion by the kidneys, and changes 
in the blood, may require greater amounts of the drug to achieve the same effect. This is why 
gestational-age based dosing of unfractionated heparin is considered in pregnancy. However, 
this is not well studied. We want to compare these two doses of unfractionated heparin to 
evaluate the safest dose for prophylactic anticoagulation of pregnant patients with prolonged 
hospitalizations.  
 
How long will the research last and what will I need to do? 
We expect that you will be in this research study from the time you are recruited until you are 
discharged from the hospital or until you are delivered (if you are admitted for the remainder of 
your pregnancy).  
 
This will be a randomized control trial, which means all participants will be randomly assigned to 
one of two groups, like flipping a coin. Women assigned to the first group will receive the 
standard dose of unfractionated heparin and women assigned to the second group will receive 
the gestational age-based dose of unfractionated heparin. We ask all participants to be open to 
being assigned to either group because you will not be able to choose or switch groups.  
 
Unfractionated heparin will be administered to you and you will undergo serial blood draws to 
monitor the blood clotting parameters while you are receiving the medication. This is part of the 
“standard of care,” meaning if you elect to not participate in the study your medical team will 
recommend administration of unfractionated heparin at the gestational age-based dosing and 
you will undergo serial blood draws for monitoring. By being a part of the study, you will receive 
either the standard dose or the gestational age-based dose of unfractionated heparin and the 
blood draw results will be collected by the study team. More detailed information about the study 
procedures can be found under “WHAT WILL HAPPEN IF I TAKE PART IN THIS STUDY?”. 
 
What kinds of risks or discomforts could I expect? 
Like all medications, unfractionated heparin has the potential to cause side effects. The most 
common side effects are bleeding or bruising and redness and swelling around the puncture 
site. Rare side effects include hypersensitivity to the medication and thrombocytopenia. 
Unfractionated heparin does NOT cross the placenta and is considered safe in pregnancy. 
Because your medical team will recommend receiving unfractionated heparin as part of 
standard hospital protocol, participation in this study does not pose an increased risk in 
exposure to unfractionated heparin. More detailed information about the risks of this study can 
be found under “WHAT KINDS OF RISKS OR DISCOMFORTS COULD I EXPECT? (Detailed 
Description).” 
 
Are there any benefits if I participate? 
This study may show that standard dosing is effective in preventing blood clots in pregnancy 
without the increased risk of a higher dose such as bleeding and restrictions on receiving 
epidurals. If you are randomized into group 1 (standard dosing), then you may directly benefit by 
receiving the lower dose. Otherwise, you will not directly benefit from participation in this 
research study. Your participation in this research may help us learn more about the appropriate 
Protocol ID:IRB#20-001799    UCLA IRB Approved   Approval Date: 10/19/2021   Through: 10/12/2022   Committee: Medical IRB 1


dosing of unfractionated heparin for venous thromboembolism prophylaxis, which would benefit 
future pregnant patients.  
 
What other choices do I have if I don’t want to participate?  
Participation in research is completely voluntary. You can decide to participate or not to 
participate.  
 
You may wish to talk to your treating physician about your choices before deciding if you will 
take part in this study. If you decide not to participate in this study, your other choices may 
include: 
• 
Declining prophylactic anticoagulation and receiving no unfractionated heparin at this 
time. 
• 
Receiving gestational age-based dosing of unfractionated heparin without being in this 
study. 
 
Disclosure Statement  
Your health care provider may be an investigator of this research protocol, and as an 
investigator, is interested in both your clinical welfare and in the conduct of this study. You are 
not under any obligation to participate in any research project offered by your clinician. 
 
How many people will take part in this study? 
We plan to enroll 46 pregnant patients to take part in this study.  
 
WHAT WILL HAPPEN IF I TAKE PART IN THIS STUDY? 
If you agree to participate in the study: 
• 
Standard lab tests will be performed using your blood sample to make sure that it is safe 
for you to receive unfractionated heparin and continue in the study. 
• 
You will be randomized into one of the two study groups described below.  
Randomized means that you are assigned to a group by chance (like a flip of a coin). A 
computer program will place you in one of the groups. Neither you nor the researchers 
can choose the group you will be in. You will have an equal chance of being placed in 
any group.  
o If you are in group 1, you will receive the standard dose of unfractionated 
heparin. 
▪ 
5,000 units subcutaneous injection every 12 hours (no matter what 
gestational age) 
o If you are in group 2, you will receive the gestational age-based dose of 
unfractionated heparin. 
▪ 
1st trimester (less than 14 weeks of gestation): 5,000 units subcutaneous 
injection every 12 hours  
▪ 
2nd trimester (14-28 weeks of gestation): 7,500 units subcutaneous 
injection every 12 hours 
▪ 
3rd trimester (greater than 28 weeks of gestation): 10,000 units 
subcutaneous injection every 12 hours  
• 
You will undergo the following blood draws to monitor the effects of unfractionated 
heparin. Each collection will be 10 ml of blood (approximately one tablespoon each 
time). As a reference, about 30 tablespoons of blood are taken  at one time when a 
person donates blood.  
o After the 2nd dose of unfractionated heparin 
o After the 4th dose of unfractionated heparin 
Protocol ID:IRB#20-001799    UCLA IRB Approved   Approval Date: 10/19/2021   Through: 10/12/2022   Committee: Medical IRB 1


o After the 10th dose of unfractionated heparin  
o Every 7 days after the 10th dose of unfractionated heparin 
• 
The lab tests performed on the collected blood samples are standard of care and are 
required to monitor you while receiving unfractionated heparin. The results of the tests 
will be provided to you.  
• 
If the blood draw measurements demonstrate that your coagulation level is elevated, the 
study team will decrease the dose of unfractionated heparin or hold the medication per 
the study protocol to ensure safety.  
• 
After the 10th dose of unfractionated heparin and then every 7 days while you are 
receiving the medication, the study team will formally ask you if you are experiencing 
any side effects from the medication.  
• 
The study team will collect information from your medical records. Examples include 
your age, sex, race/ethnicity, details of your labor and delivery course, and overall health 
in your pregnancy. 
 
WHAT KINDS OF RISKS OR DISCOMFORTS COULD I EXPECT? (Detailed 
Description) 
Risks of Medication  
Unfractionated heparin has the potential to cause side effects. The most common side effects 
are bleeding or bruising and redness and swelling around the puncture site. Rare side effects 
include hypersensitivity to the medication (hives, fever, swelling of throat, difficulty breathing) 
and thrombocytopenia. If significant side effects occur, the medication will be discontinued. 
Unfractionated heparin does not cross the placenta and is considered safe in pregnancy without 
any increased risk of fetal malformation. Unfractionated heparin is administered as a 
subcutaneous injection, which means an injection under the skin, and may cause temporary 
pain after administration. Because your medical team will recommend administration of 
unfractionated heparin as part of standard hospital protocol for prophylactic anticoagulation, 
participation in the study does not pose an increased risk in exposure to unfractionated heparin. 
 
Currently both standard dose and gestational age-based dose of unfractionated heparin are 
recommended for prophylactic anticoagulation of hospitalized antepartum patients. Because 
standard dosing is lower than gestational age-based dosing, it might be less effective in 
preventing blood clots. However, the overall risk of developing a blood clot is very low (less than 
2%), and standard dosing is the dose recommended outside of pregnancy. Gestational age-
based dosing is higher and theoretically may limit your ability to receive an epidural. However, 
we will be monitoring you closely with serial blood samples and decrease the dose if the lab 
results are elevated in order to decrease this risk. At UCLA, the gestational age-based (higher) 
dosing is the current standard of care because of the theoretical changes in pregnancy that may 
result in requiring greater amounts of heparin to achieve the same effect. If you are not in the 
study, your medical team will recommend gestational age-based dosing as part of standard 
hospital protocol for prophylactic anticoagulation, so those assigned to group 2 are not exposed 
to an increased risk.   
 
There may be risks associated with the drug/treatment that are as yet unknown, but that the 
researcher will advise you if any new information becomes available that might affect your 
desire to participate in the study.  
 
Risks of Study Procedures 
Possible side effects from blood draws include temporary discomfort from the needle stick, 
bruising and, rarely, infection and fainting.  
Protocol ID:IRB#20-001799    UCLA IRB Approved   Approval Date: 10/19/2021   Through: 10/12/2022   Committee: Medical IRB 1


 
Risks Associated with Randomization 
You will be assigned to a study group at random (by chance). Your assignment is based on 
chance (like a coin flip) rather than a medical decision made by researchers. The study group 
you are assigned to might not be the group you would before to be in. It might also prove to be 
less effective or have more side effects than the other study group, or standard treatments 
available for your condition.  
 
HOW WILL INFORMATION ABOUT ME AND MY PARTICIPATION BE KEPT 
CONFIDENTIAL? 
The study doctor and study staff will do their best to make sure your private information is kept 
confidential. Any information that is obtained in connection with this study and that can identify 
you will be handled as confidentially as possible. All identifiable information about you will be 
replaced with a code. A list linking the code and your identifiable information will be kept 
separate from the research data and only available to the research team. All research data and 
records will be physically and electronically secured. As with any use of electronic means to 
store data, there is a risk of breach of data security.  
 
The research team, authorized UCLA personnel, the study sponsor (remove if not applicable), 
and regulatory agencies such as the Food and Drug Administration (FDA), may have access to 
study data and records to monitor the study.  Research records provided to authorized, non-
UCLA personnel will not contain identifiable information about you. Publications and/or 
presentations that result from this study will not identify you by name. 
 
Employees of the University may have access to identifiable information as part of routine 
processing of your information, such as lab work or processing payment. However, University 
employees are bound by strict rules of confidentiality. 
 
Because this study involves the treatment of a medical condition and/or medical procedures, a 
copy of this consent form will be placed in your medical record.  This will allow the doctors that 
are caring for you to obtain information about what medications and/or procedures you are 
receiving in the study and treat you appropriately.  
 
 
USE OF DATA AND SPECIMENS FOR FUTURE RESEARCH 
The researchers intend to keep the research data and records indefinitely for future research. 
Your data, including coded data, may be kept for use in future research, but will not be shared 
outside the study team. 
 
ARE THERE ANY COSTS FOR TAKING PART IN THIS STUDY? 
There will be no additional cost to you or your health plan as a result of your participation in this 
study. Items and services described in this consent form would have occurred regardless of 
your participation in this study or, if research-related, will be provided to you at no cost.  
 
WILL I BE PAID FOR MY PARTICIPTION? 
You will not be paid for your participation in this research study. You will not be reimbursed for 
any out-of-pocket expenses, such as parking or transportation fees. 
 
WHAT OTHER THINGS SHOULD I CONSIDER BEFORE PARTICIPATION? 
Use of Specimens: 
Protocol ID:IRB#20-001799    UCLA IRB Approved   Approval Date: 10/19/2021   Through: 10/12/2022   Committee: Medical IRB 1


Any specimens (e.g., tissue, blood, urine) obtained for routine lab testing will be discarded or 
destroyed once they have been used for the purposes described in the protocol.  
 
WHO CAN I CONTACT IF I HAVE QUESTIONS ABOUT THIS STUDY? 
The Research Team: 
If you have any questions or concerns about the research or your participation in this study, 
please contact:  
 
Rashmi Rao, MD – Principal Investigator  
Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine  
10833 Le Conte Ave. 
Los Angeles, CA 90095 
Phone: 310-794-7274 
 
Thalia Wong, MD – Co-Investigator  
Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine 
10833 Le Conte Ave.  
Los Angeles, CA 90095 
Phone: 310-210-2246 
 
UCLA Office of the Human Research Protection Program (OHRPP): 
If you have questions about your rights while taking part in this study, or you have concerns or 
suggestions and you want to talk to someone other than the researchers about the study, you 
may contact the UCLA OHRPP through the following: 
 
Phone: (310)206-2040 
E-mail: participants@research.ucla.edu  
U.S. mail: UCLA OHRPP, Box 951406, Los Angeles, CA 90095-1406 
 
Public Information about this Study: 
ClinicalTrials.gov is a website that provides information about federally and privately supported 
clinical trials. A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This website will not include information that can identify you. At most, 
the website will include a summary of the results. You can search this website at any time.  
 
WHAT HAPPENS IF I BELIEVE I AM INJURED BECAUSE I TOOK PART IN THE STUDY? 
 
It is important that you promptly tell the researchers if you believe that you have been injured 
because of taking part in this study. You can tell the researcher in person or call him/her at the 
number(s) listed above. 
  
If you are injured as a result of being in this study, UCLA will provide necessary medical 
treatment. The costs of the treatment may be covered by the University of California or the 
study sponsor [sponsor name], or billed to you or your insurer just like other medical costs, 
depending on a number of factors. The University and the study sponsor do not normally 
provide any other form of compensation for injury.  For more information about this, you may 
call the UCLA Office of the Human Research Protection Program at 310-206-2040 or send an 
email to participants@research.ucla.edu. 
 
 
WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY? 
Protocol ID:IRB#20-001799    UCLA IRB Approved   Approval Date: 10/19/2021   Through: 10/12/2022   Committee: Medical IRB 1


Taking part in this study is your choice. You can choose whether or not you want to participate. 
Whatever decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits. 
• 
You have a right to have all of your questions answered before deciding whether to take 
part. 
• 
Your decision will not affect the medical care you receive from UCLA. 
• 
If you decide to take part, you can leave the study at any time. 
• 
If you decide to stop being in this study you should notify the research team right away. 
The researchers may ask you to complete some procedures in order to protect your 
safety.  
• 
If you decide not to take part, you can still receive medical care from UCLA. 
 
HOW DO I INDICATE MY AGREEMENT TO PARTICIPATE? 
If you agree to participate in this study you should sign and date below. You have been given a 
copy of this consent form and the Research Participant’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. 
 
 
SIGNATURE OF THE PARTICIPANT 
 
______________________________________ 
Name of Participant 
 
______________________________________ 
______________________ 
Signature of Participant 
 
 
 
 
Date 
 
 
 
SIGNATURE OF PERSON OBTAINING CONSENT 
 
______________________________________ 
______________________ 
Name of Person Obtaining Consent 
 
 
Contact Number 
 
______________________________________ 
______________________ 
Signature of Person Obtaining Consent  
 
Date 
 
 
 
 
 
 
 
 
 
 
  
 
Protocol ID:IRB#20-001799    UCLA IRB Approved   Approval Date: 10/19/2021   Through: 10/12/2022   Committee: Medical IRB 1


 
Protocol ID:IRB#20-001799    UCLA IRB Approved   Approval Date: 10/19/2021   Through: 10/12/2022   Committee: Medical IRB 1

SAP_005.pdf: 
Title of Study: Heparin Prophylaxis Dosing for Antepartum Hospitalizations (HEPDOSE) 
 
NCT Number: NCT04635839 
 
Document Date: June 27, 2022 
 
Document: Statistical Analysis Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Traditional univariate analysis was performed for our primary and secondary outcomes 
with Chi-square or Fisher exact test for categorical variable and t-test or Wilcoxon rank-sum test 
for continuous variables. A logistic regression analysis was performed to further assess the 
association of elevated aPTT with gestational age-based dosing of unfractionated heparin relative 
to standard dosing. We also performed a multivariate logistic regression to adjust for 
confounders. Confounders included in the model were a priori covariates that potentially could 
affect the response to unfractionated heparin along with baseline characteristics from our 
univariate analyses comparing study arm groups that had a p value < 0.2. Via a stepwise 
regression, none of the variable demonstrated a significant effect on our primary outcome. 
However, for our final model we elected to adjust for creatinine and obesity based on clinical 
relevance and a priori knowledge of these factors being potential confounders that may not have 
been detected in our study cohort due to the small sample size.  
 Statistical significance was defined as a p-value of < 0.05 or non-overlapping 95% 
confidence intervals (CI). All analyses were conducted using Statistical Analysis Software 
(SAS), version 9.4 (Copyright 2013, SAS Institute, Inc. Cary, NC).