Study protocol. TRAAP – TRAnexamic Acid for Preventing postpartum hemorrhage after vaginal delivery: a multicenter randomized, double-blind, placebo

Recruitment and allocation

Inclusion criteria

Age???18 years

Planned vaginal delivery

Term???35 weeks of gestation

Singleton pregnancy

Informed consent form signed

Exclusion criteria

History of venous (deep vein thrombosis and/or pulmonary embolism) or arterial (angina
pectoris, myocardial infarction, stroke) thrombosis

History of epilepsy or seizure

Any known cardiovascular, renal, or liver disorders

Autoimmune disease

Sickle cell disease

Severe hemorrhagic disease

Placenta previa

Abnormally invasive placenta (placenta accreta/increta/percreta)

Abruptio placentae

Eclampsia, HELLP syndrome

Multiple pregnancy

In utero fetal death

Administration of low-molecular-weight heparin or antiplatelet agents during the
week before delivery

Poor understanding of the French language

Individual information on the trial will be provided to women in late pregnancy by
obstetricians and midwives during prenatal visits or by anesthetists during the systematic
anesthesia visit, or both. This information will be repeated when the women arrive
in the delivery room; each woman will then confirm her participation and provide informed
written consent before delivery, when, in the investigator’s opinion once she has
reached at least 4 cm of cervical dilatation, she is likely to have a vaginal delivery.

The randomization will be centralized and stratified by center and balanced in blocks
of variable sizes. Once a woman has been included, through the filing of an electronic
case report directly by internet (Clinsight software), she will retain her randomization
number (if it has been assigned to her) even if she withdraws from the study or refuses
randomization afterwards.

Women will be randomized to receive either 1 g of TXA (Sanofi Aventis, Paris, France;
Marketing authorization number: 3400931157618 [1974, RCP rév 02.04.2010]) or placebo
(normal saline, Fresenius Kabi, Sèvres, France; Marketing authorization number: 34009415
73941). The Angers Clinical Research Unit will create the randomization list for allocations
to the TXA and control groups. This list will be transmitted to the pharmacy department
of CHU Angers, which belongs to the PPRIGO hospital pharmacists’ consortium (Production
Pharmaceutique pour la Recherche Institutionnelle du Grand Ouest). The blinded products
will be prepared by the Angers CHU pharmacy according to GMP for hospital pharmacies
(BPP 2007), which will provide numbered and labeled boxes, each containing a 10-mL
vial of the study drug (1 g of TXA or placebo according to the randomization number).
All boxes and vials will be identically labeled, with the study number being the only
differentiating feature between different drug packs. This will ensure the woman’s
safety and the blinding of all participants, including obstetric staff.

Intervention

The intervention will be the intravenous administration of a 10-mL blinded vial of
the study drug (either 1 g of TXA or placebo, according to the randomization group),
slowly (over 30–60 sec), in the 2 min after birth and the routine prophylactic oxytocin,
and after the cord has been clamped, all generally by the midwife (but sometimes by
the anesthesiologist or obstetrician, depending on availability).

Except for the content of the study drug vial, all aspects of management of the third
stage will be identical in both arms:

Routine prophylactic intravenous injection of 5 IU oxytocin at delivery of the anterior
shoulder or within 2 min of birth, as recommended in the national clinical practice
guidelines issued by the French College of Gynecologists and Obstetricians 50].

Placement of a graduated (100 mL graduation) collector bag just after birth, left
in place for at least 15 min and then until the birth attendant judges that bleeding
has stopped. When a woman is included in the trial, a bag will be prepared and ready
to be put in place as soon as the baby is born and placed on the mother’s belly; if
needed, a second staff person will be present to help in managing both the baby and
the bag. This will make it possible to collect and measure vaginal blood loss objectively
during the immediate postpartum 14].

Manual removal of the placenta at 30 min after birth if not expelled, in the absence
of bleeding.

Rapid suturing of the episiotomy, in accordance with good clinical practices.

Systematic use of uterotonic drugs after the third stage of labor is not recommended.

Controlled cord traction (CCT) will be left to the discretion of the practitioner
since its use in the management of placental expulsion has been shown to have no significant
effect on the incidence of PPH or other markers of postpartum blood loss 14].

If PPH occurs, standardized management will be provided according to the department’s
protocol. In particular, the use of TXA for the treatment of PPH will be allowed and
left to the discretion of the practitioner, according to the department’s protocol.

Before inclusions begin, a meeting will be organized in each maternity unit to verify
the attendants’ agreement to and understanding of the protocol and their ease in practicing
the relevant procedures.

Outcome measures

Primary outcome measure

The primary outcome of the trial is the incidence of PPH, defined by blood loss???500 mL,
measured with a graduated collector bag. The term “measured” implies an objective
determination of the blood volume lost, in contrast to a simple visual estimate, which
has been shown unreliable in several studies 14], 51]–55].

The systematic use of a graduated collector bag for blood, placed under the woman’s
buttocks just after delivery of the child, will allow an objective measurement of
the blood lost through the vagina in the immediate postpartum period.

The practical feasibility of the use of such a bag was shown in the TRACOR trial 14]. This bag shall be left in place for at least 15 min and afterwards until the birth
attendant is no longer concerned about blood loss, and judges that the woman’s condition
allows her to stretch out. This criterion will be measured during the immediate postpartum
surveillance in the delivery room, in both groups.

Secondary outcomes

Secondary outcome measures describing postpartum blood loss

Clinical

mean measured blood loss at 15 min after birth (the collector bag must be left in
place at least 15 min to have one measure of blood loss at the same time point for
all women)

mean measured total postpartum blood loss (at bag removal)

incidence of severe PPH, defined by measured blood loss???1000 mL.

proportion of women requiring supplementary uterotonic treatment, including sulprostone

incidence of postpartum transfusion (until discharge)

incidence of arterial embolization and emergency surgery for PPH.

Laboratory

mean change in peripartum hemoglobin (difference between Hb before delivery and at
D2)

mean change in peripartum hematocrit (difference between Ht before delivery and on
D2).

For both indicators, the pre-delivery reference examination will be the last routine
blood count in the last trimester of the pregnancy. A blood sample will be taken from
all women included in the trial on the second day postpartum for the measurement of
peripartum Hb and Ht and the calculation of the change in these two indicators. If
no blood sample is available from D2, measurement of postpartum Hb and Ht will be
assessed from a D3 blood sample, if available. If no blood sample is available from
D2 or D3, measurement of postpartum Hb and Ht will be assessed from a D1 blood sample,
if available.

The occurrence of potential adverse effects of TXA:

Clinical

Hemodynamic parameters (heart rate, blood pressure) 15, 30, 45, 60 and 120 min after
delivery.

the occurrence of potential mild adverse effects of TXA in the delivery room:

? nausea

? vomiting

? phosphenes

? dizziness

the occurrence of potential severe adverse effects of TXA up to three months of postpartum:

? deep vein thrombosis, if the diagnosis is confirmed by Doppler ultrasound

? pulmonary embolism, if the diagnosis is confirmed by radiological examinations.

? myocardial infarction

? seizure

? renal failure needing dialysis

? any other unexpected adverse events.

These events will be checked by the medical team during the hospitalization and then
on D90 by a telephone interview of each woman. In the event that the woman cannot
be reached, at least 10 calls at different hours over the course of the week will
be made to minimize loss to follow-up. In cases of severe adverse effects reported
by a woman after the hospital discharge, objective data will be collected from medical
files, transmitted either by the woman herself or her general practitioner.

Laboratory

urea and creatinemia, prothrombin time (PT), active prothrombin time (aPTT), aspartate
and alanine transaminase, and total bilirubin at D2

Women’s satisfaction and psychological status

These will be assessed by a self-administered questionnaire on day 2 postpartum and
by mail on day 60.

Statistical analysis

Data analysis and reporting will follow the CONSORT guidelines for randomized controlled
trials and will be conducted with the trial statistician and researchers blinded to
group status. The two groups will be compared for women’s demographic characteristics
and standard risk factors for PPH. Then we will seek, in an intention-to-treat analysis,
the existence of a “TXA effect”, that is, a difference between the two groups for
the primary outcome measure and the secondary outcome measures. For secondary outcomes
that are available for women who had a cesarean delivery after randomization (percentage
of women requiring supplementary uterotonic agents, mean change in peripartum hemoglobin,
mean change in peripartum hematocrit, incidence of postpartum transfusion, arterial
embolization, and emergency surgery), a secondary analysis will be conducted that
includes these women. The comparisons will use nonparametric statistical tests when
required by the constraints of population size or distributions. Comparisons of the
categorical variables will use chi2 and Fisher exact tests, as appropriate. We will
use analysis of variance and Kruskal and Wallis’s nonparametric test for the continuous
variables. Effects will be measured as relative risks, with their 95 % confidence
intervals.

The analysis plan includes an intermediate statistical analysis when half of the planned
women have been included to ensure there is no significant difference in the adverse
events between the two groups.

Feasibility

The majority of the participating centers have previously worked together in a French
multicenter randomized controlled trial that aimed to assess the effect of controlled
traction of the cord on the prevention of PPH (TRACOR trial) 17]. During a one-year period, they together randomized 4068 women with vaginal deliveries
and demonstrated their capacity to conduct and perform a RCT regarding the prevention
of PPH. Moreover, all the participating centers belong to the GROG (Groupe de Recherche
en Obstétrique et Gynécologie) national network.

Sample size

In the recent RCT (TRACOR trial), involving the same participating centers, mentioned
above, comparison of the efficacy of the controlled cord traction and standard placenta
expulsion in preventing PPH showed that the PPH rate (measured postpartum blood loss
of 500 mL or more) was 10.0 % (402/4013), with no significant heterogeneity between
centers 14].

Accordingly, for this study, we assumed a 10 % incidence of PPH in the absence of
TXA. To show a relative reduction of at least 30 % in this incidence in the TXA arm—that
is, an incidence of 7 % or less in this arm, with a?=?0.05, 1-ß?=?0.90, and a bilateral
test, the study requires 1814 women with vaginal deliveries in each group. Given the
expected proportion of women with a cesarean delivery in labor after randomization
(estimated at 5 % to 10 % [6.8 % in the TRACOR trial] 14]), the total number of randomized women will be greater in order to include the needed
number of women with vaginal deliveries: 2000 women will be included in each group,
for a total of 4000 participants.

Timetable

The participating maternity units deliver 21,500 infants a year. We consider that
70 % of women will meet the criteria for inclusion in the participating maternity
units, excluding scheduled cesareans, cesareans in early labor, deliveries before
35 weeks, and multiple pregnancies. We add to these categories the cesareans decided
at the end of labor (about 5 % of deliveries), after inclusion but for which no primary
outcome measure will be available, and which therefore cannot be included in the analysis
— even for intention to treat. Overall, 13,975 annual deliveries (65 % of the total)
may possibly be included in the principal analysis. An inclusion period of 20 months
should make it possible to recruit 4,000 women, if we assume a participation rate
of at least 17.2 %. This participation rate appears realistic in light of the recruitment
in the TRACOR trial in the labor wards of all the participating centers 17].

The total duration of the trial will be 23 months, including 20 months of inclusion
and 3 months of follow-up in the postpartum period (assessment of thromboembolic and
any unexpected adverse events).

The total duration of the project will be 34 months, including:

6 months for ethics approval, signatures of agreements between the participating
centers and training the staff in the management methods required by the protocol
for the third stage of labor.

23 months for the trial, with an inclusion period of 16 months and a follow-up period
of 3 months.

5 months after the end of the inclusion period will be devoted to finalizing the
data collection and entry, database cleaning, and analysis.

Ethics committee approval

This study was approved by the West II Committee for the Protection of Research Subjects
(Ethics Committee) on August 21, 2014 (2014/09), and by the French Health Products
Safety Agency (ANSM) on August 6, 2014 (2014-001748-39).

Data management

Each investigator will be responsible for ensuring data, which will be completed by
the clinical research technician throughout the trial, with Clinsight software. The
electronic case report file for each woman will contain 5 components:

1 completed by the clinical research technician from the obstetric file: woman’s
characteristics, course of the pregnancy, labor, and delivery

1 completed by the clinical research technician about the postpartum events after
leaving the delivery room, and the results of the blood count on D2

1 questionnaire about women’s satisfaction on D2 postpartum, completed by the women,
with responses entered secondarily in the electronic file by the clinical research
technician.

1 questionnaire about the women’s satisfaction and psychological status on D60 postpartum,
sent by the technician to the women and completed by them, with responses entered
secondarily in the electronic file by the clinical research technician.

1 questionnaire about the occurrence of thromboembolic and any other unexpected events
at 12 weeks in postpartum, completed by the clinical research technician during a
telephone interview with the woman, with responses secondarily entered in the electronic
file by the technician.

Data will be collected for women who have a cesarean delivery after randomization,
data will be collected.

The data management and statistical aspects will be handled centrally by the Angers
University Hospital (Department of Clinical Research and Development – Methodology
and Biostatistics Unit) with the Scientific Director of the study (CDT).

Quality control will be conducted according to the standard operating procedures of
the sponsor, Angers University Hospital. The research in the investigational centers
and management of subjects will comply with the Declaration of Helsinki and Good Clinical
Practices. An independent data monitoring committee including only independent members
will be in charge of controlling the quality and the safety of the trial procedures
and of the data collected. Clinical research assistants will conduct monthly visits
in each investigative center and report to the data monitoring committee. During these
onsite inspections and in accordance with Good Clinical Practices, the following items
will be reviewed:

Compliance with the research protocol and the procedures defined therein

Verification of the patients’ informed consents, for all women included

Examination of the source documents and their comparison with the data reported in
the electronic case report files (CRFs), for the accuracy and consistency of the data
and the missing data, performed on a random sample of 10 % of participating women.

End-of-trial visit: archiving of research documents.

Trial steering committee

A trial steering committee will be set up which will have overall supervision of the
trial. It will meet before the trial starts and then at least every 6 months until
completion. A meeting of the TSC will be held within a month of every Safety Monitoring
Committee meeting to consider their recommendations.

Safety consideration

An independent Safety Monitoring Committee will also be formed. They will meet at
minimum yearly to examine recruitment figures, baseline data, retention and adverse
events. The Safety Monitoring Committee will review the result of the interim analysis
of safety data when half of the planned participants have been recruited.

Suspected unexpected serious adverse reactions (SUSARs) will be recorded and reported
using the ANSM approved SUSAR form. SUSARs include maternal death, surgery (other
than cesarean delivery) in the 12 weeks following randomization, transfusion of more
than 4 units of blood, admission to an intensive care unit, deep vein thrombosis,
pulmonary embolism, myocardial infarction, seizure, renal failure defined by the need
for dialysis, or suspected drug reactions. In the event of a SUSAR the form will be
completed by the local trial coordinator and faxed to the trial coordinating center
at the Angers University Hospital within 72 h. From there the copies of the form will
be sent to the trial statistician and the chair of the Safety Monitoring Committee.
The Safety Monitoring Committee will have the power to ask to break the blinding,
whereas the study investigators will remain blinded to the allocated treatment. The
ANSM, the trial sponsor and the Chair of the Ethics Committee will also be informed
by the Safety Monitoring Committee if considered appropriate, in particular in cases
of strong suspicion of SUSARS related to the Investigational Medicinal Products. Finally,
should the Safety Monitoring Committee believe it necessary, it is authorized to recommend,
to the Scientific Committee that the trial be stopped.