Postpartum Hemorrhage Reduction With Oral Tranexamic Acid (PROTECT): a Multicenter Randomized Controlled Trial
Phase: PHASE4
Conditions: PPH
Sponsor: Karolinska Institutet

 
 
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Form FHS015: Research Protocol – Section C 
 
Title: 
 Postpartum hemorrhage reduction with oral 
tranexamic acid (PROTECT): a multicenter 
randomized controlled trial 
Date: 
  22 April 2024 
Protocol Version: 
 6.0 
Eudra-CT no: 
 2020-002015-22 
Swedish MPA Number:  
 5.1-2022-46998 
Swedish Ethical Review  
Authority Number:  
2020-06618 / 2022-01257_02 (minor amendment) 
Investigational product:  
Tranexamic Acid (TA) oral solution 
 
Indication: 
 Prophylactic medication for the prevention post-partum 
hemorrhage in vaginal delivery 
 
Study Phase: 
 Phase III South Africa / Phase IV Sweden 
 
Study sites Sweden:   
Södersjukhuset, Stockholm 
 
 
 
 
Lund University Hospital, Lund 
 
 
 
 
Hudiksvall Hospital 
Study Sites South Africa: 
Mowbray Maternity Hospital, Cape Town 
 
 
 
 
Khayelitsha District Hospital, Cape Town 
 
Main Principal investigator 
Margit Endler, MD PhD, Associate Professor 
Department of Women and Children´s Health, 
Karolinska Institutet, Tomtebodavägen 18, 171 76 
Stockholm, Sweden 
 
 
margit.endler@ki.se,  Tel +46 706 747227 

 
 
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and Department of Public Health, University of 
Cape Town, Anzio Road, 7925 Observatory, South 
Africa, margit.endler@uct.ac.za Tel +27 78 
9106286 
Principal investigator, South Africa  
Justus Hofmeyr, Professor MD PhD, 
research consultant, East London Hospital 
Complex, East London, South Africa 
 
justhof@gmail.com, Tel +27 0832809402 
 
Co-investigators 
Gita Strindfors, MD, site co-investigator Södersjukhuset, 
Stockholm, Sweden 
 
Lars Thurn, MD PhD, site co-investigator Lund 
University Hospital, Lund, Sweden 
 
Zoltan Zavaczki, MD PhD, site co-investigator Gävleborg 
Hospital District, Gävleborg, Sweden 
 
Pelle Lindqvist, Professor MD PhD, research consultant 
 
Chantal Stewart, MD PhD, site subinvestigator Mowbray 
Maternity, Cape Town, South Africa 
 
Christine Els, MD, site subinvestigator Khayelitsha 
District Hospital, Khayelitsha, South Africa 
 
 

 
 
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List of abbreviations 
 
TA 
Tranexamic Acid 
RCT 
Randomized Controlled Trial 
PPH 
Postpartum Hemorrhage 
Hb 
Hemoglobin 
IMP 
Investigational Medicinal Product 
EVF 
Erythrocyte Volume Fraction (Hematocrit) 
MCV 
Mean Corpuscular Volume 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
ITT 
Intention to treat 
PP 
Per Protocol 
AE 
Adverse Event 
SAR 
Serious Adverse Reaction 
AR 
Adverse Reaction 
RSI 
Reference Safety Information 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
SAE 
Serious Adverse Event 
CRF 
Case Report File 
MPA 
Medical Products Agency (Läkemedelsverket) 
RERB 
Regional Ethical Review Board 
SAPHRA 
South African Health Products Regulatory Authority 
CIOMS 
Council for International Organizations of Medical Sciences 

 
 
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Table of Contents  
  
1. 
Purpose of the study  
 
 
 
 
 
 
6 
2. 
Background   
 
 
 
 
 
 
 
6 
3. 
Methodology  
 
 
 
 
 
 
 
7 
3. 1 
Study Design   
 
 
 
 
 
 
7 
3.2 
Characteristics of the study population 
 
 
 
8 
3.2.1 Inclusion and Exclusion Criteria 
 
 
 
8 
3.3 
Intervention 
 
 
 
 
 
 
 
9 
 
3.3.1 Investigational Medicinal Product 
 
 
 
9 
3.4 
Outcomes  
 
 
 
 
 
 
 
9 
3.5 
Recruitment and enrolment 
 
 
 
 
 
10 
3.6 
Randomization 
 
 
 
 
 
 
10 
3.7 
Study procedures 
 
 
 
 
 
 
11 
4. 
Data Collection Methods and Monitoring  
 
 
 
12 
4.1 
Measurement of outcomes 
 
 
 
 
 
12 
4.2 
Appropriateness of intervention 
 
 
 
 
13 
4.3 
Measurement of background variables 
 
 
 
14 
4.4  
Data analysis  
 
 
 
 
 
 
15 
4.4.1 Sample size calculation  
 
 
 
 
15 
 
4.4.2 Handlings of dropouts and missing data 
 
 
15 
 
4.5 
Research team qualifications and selection of study sites 
 
16 
 
4.6 
Data Safety and Monitoring Plan 
 
 
 
 
18 
 
 
4.6.1 Display of adverse events 
 
 
 
 
18 
 
 
4.6.2 Analysis of adverse events 
 
 
 
 
19 
 
 
4.6.3 Deaths and other serious adverse events (SAEs)  
 
19 
 
 
4.6.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
20 
 
 
4.6.5 Reporting of AEs, SAEs and SUSARs  
 
 
21 
 
 
4.6.6 Unblinding 
 
 
 
 
 
 
22 
 
 
4.6.7 Stopping Criteria 
 
 
 
 
 
23 
 
 
4.6.8 Study Monitoring 
 
 
 
 
 
23 
 
4.7 
Data confidentiality  
 
 
 
 
 
24 
5. Description of Risks and Benefits 
 
 
 
 
 
24 
 
5.1 Potential risks and discomforts 
 
 
 
 
 
25 
 
5.2 Risk classification  
 
 
 
 
 
 
25 
 
5.3 Minimizing risk  
 
 
 
 
 
 
27 
 
5.4 Potential benefits  
 
 
 
 
 
 
28 
 
5.5 Alternatives to participation 
 
 
 
 
 
28 
 
5.6 Harm : Benefit ratio 
 
 
 
 
 
 
29 
6. Informed consent  
 
 
 
 
 
 
 
30 
 
6.1 Informed consent process  
 
 
 
 
 
30 
 
6.2 Capacity to comprehend and assessment of vulnerability 
 
31 
 
6.3 Comprehension of information 
 
 
 
 
 
31 
 
6.4 Withholding information  
 
 
 
 
 
31 
 
6.5 Consent and assent forms  
 
 
 
 
 
31 
 
6.6 Privacy and confidentiality 
 
 
 
 
 
32 

 
 
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7.  Reimbursement  
 
 
 
 
 
 
 
32 
 
8.  Emergency care and insurance for research-related injury  
 
32 
9.  What happens at the end of the study  
 
 
 
 
33 
10. References 
 
 
 
 
 
 
 
 
35 
11. List of Appendix Material 
 
 
 
 
 
 
37 
 
 
 
 

 
 
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1.  Purpose of the Study 
 
The main purpose of the study is to evaluate the effect of orally administered TA 
compared to placebo on rate of postpartum hemorrhage (PPH) >=500ml assessed by 
weight in vaginal deliveries. 
Our secondary aims are: 
▪ To evaluate the effect of orally administered TA compared to placebo on mean 
blood loss, pre-postpartal Hb difference  ≥10 units, severe PPH (>=1000ml), and 
the need of blood transfusion 
▪ To evaluate feasibility, i.e. adherence to administration of oral TA compared to 
placebo. 
▪ To evaluate the acceptability of orally administered TA compared to placebo among 
women giving birth and providers 
▪ To evaluate the safety of administration of oral TA compared to placebo 
▪ To assess the effect of the intervention on PPH among the subgroup of women with 
anemia 
▪ To assess the effect of the intervention on PPH according to time of administration 
in relation to delivery of the child. 
 
2. Background 
 
Severe PPH is the leading cause of maternal death worldwide especially in developing 
countries (1). Obstetric hemorrhage is one of the leading cause of preventable maternal 
deaths in South Africa according to the latest confidential inquiry on maternal deaths 
(2).  The uterus and placenta are highly vascularized organs during pregnancy and labor 
which means that once bleeding starts it is often difficult to control. PPH increases 
maternal morbidity related to emergency interventions such as manual removal of the 
placenta, suturing of cervical or vaginal tears, embolization of uterine arteries, and 
hysterectomy as well as PPH-related complications such as anemia, postpartum 

 
 
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endometritis, venous thrombosis, and transfusion-related complications (3,4). 
Preventing PPH before onset is therefore of key importance. 
Uterotonics such as oxytocin, ergometrine and misoprostol are often used to improve 
uterine contraction during PPH (1). TA is an anti-fibrinolytic agent which blocks 
plasminogen from binding to fibrin and in doing so, inhibits the break-down of blood 
clots. This means that hemorrhage is theoretically decreased regardless of its cause. 
 
TA is a well-established and tested medication for treatment and prevention of heavy 
bleeding on the WHO list of essential medication (27). Intravenous TA (at doses 1-4g) 
reduces the rate of maternal deaths during diagnosed PPH but the prophylactic effect of 
intravenous TA on PPH after vaginal is still uncertain (4-9). A Cochrane review found a 
positive effect in rate of PPH but subsequent RCTs have shown conflicting conclusions.   
TA is recommended by for treatment of PPH by the WHO but the effect of different 
forms of oral treatment in vaginal deliveries has been scarcely studied and is a stated 
research priority by the organization (10). Oral forms of TA exists as a tablet, an 
effervescent tablet, and as an oral solution of which the former two are routinely 
prescribed and available as over the counter medications in Sweden, though not in 
South Africa. Both the tablet and the solution forms of TA are low-cost, stable at room 
temperature and easy to administer which makes them especially applicable to both low 
resource delivery settings and home- births. 
To prevent PPH, a therapeutic serum concentration of TA should coincide with the 
period immediately after delivery of the child, when the risk of PPH is greatest, 
meaning that TA should optimally be administered during the latter part of active labor. 
After oral administration to non-pregnant and pregnant individuals, maximum serum 
concentration of TA is attained after 60-180 minutes, uptake and clearance is linear and 
a serum-concentration of  >10-mg/l provides near maximal inhibition of fibrinolysis 
and levels between 5mg/l to 10mg/l are enough to attain substantial effect on 
fibrinolysis in vitro (11-14).  
The premises of the RCT are the following: 
 

 
 
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1) 
The effect of oral prophylactic TA on rate of PPH is insufficiently known 
2) 
If oral TA is effective in preventing PPH, routine administration could 
reduce maternal morbidity significantly at low risk and expense. 
 
3. Methodology 
3.1 Study Design 
This is a multicentre randomized placebo-controlled double-blinded phase IV study 
among 1000 women in Sweden and South Africa on the effect of oral tranexamic acid on 
PPH after vaginal delivery.  
3.2 Characteristics of study population 
The study will include 1000 women planned for vaginal delivery at three study sites in 
Sweden (n=500) and two study sites in South Africa (n=500) during the period March 
2023 to December 2026. 
 
3.2.1 Inclusion and exclusion criteria 
 
Inclusion Criteria 
• Women who are planned for vaginal delivery. 
• Women ≥18 years old. 
 
Exclusion Criteria 
• Preterm labor before gestational week 36+0 
 
• Ongoing treatment for venous thrombosis 
 
• Known bleeding disorder (including prolonged APTT or high INR) 
 
• History of seizures 
 
• Known hypersensitivity towards TA, 
 
• Inability to understand spoken and written English, Swedish, 

 
 
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IsiXhosa or Afrikaans (depending on the study site) 
 
• Inability to understand the contents of the written information about the 
study. 
 
3.3 Intervention 
Our intervention consists of the oral self-intake of either 20 ml (2g) of oral solution of 
TA, or 20 ml placebo, at a time when an estimated that 3-4 hours remain until delivery. 
For a primipara this should approximate the time when the cervix is dilated 8 cm, for a 
parous woman it should approximate the time when the cervix is dilated 6 cm. Cervical 
dilatation is in Sweden routinely assessed every 2 hours during delivery until the cervix is 
fully dilated and then every 30min-1hr until delivery. In South Africa vaginal exams are 
performed 4-hourly until 7 cm dilatation and 2 hourly thereafter. Participation in the 
study should not entail any additional vaginal exams compared to clinical practice. 
Timing of administration and delivery will be recorded on a study protocol. Oral solution 
TA is a non-viscous, colorless, odorless, and orange-tasting liquid. Our placebo, which 
has been developed by APL is manufactured to be non-distinguishable in viscosity, 
appearance, odor, and taste. The reason we are using an oral solution instead of an 
equivalent dose of oral tablets (4 tablets á 500mg) is that TA tablets are quite large, and 
enclosed in the rubber-like coating used to disguise the investigational medicinal product 
(IMP) from the placebo, the size is prohibitively large to ask women to swallow during 
labor.  
 
3.3.1 Investigational medicinal product 
The IMP, TA (product code SUB11214MIG), is a synthetic derivative of the amino acid 
lysine and has an antifibrinolytic effect by blocking lysine receptors on plasminogen, 
thereby preventing it from adhering to lysine molecules on the fibrin plug. This prevents 
plasminogen converting to its active form plasmin which inhibits the degradation of the 
fibrin plug. 
TA is a commonly used drug and has in multiple studies proven efficient in 
preventing and decreasing blood loss in surgery, trauma, and obstetric care without 

 
 
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increased risk of thrombosis (15, 16). It is well tolerated with few serious side effects 
(17).  
3.4 Outcomes 
Primary endpoints 
▪ Weight / volumetric estimated rate of PPH (≥500ml) 
Secondary endpoints 
▪ Pre-postpartum Hb difference equivalent to (g/L) ≥10 units 
▪ Weight-estimated rate of severe PPH (≥1000ml) 
▪ Mean blood loss (ml) 
▪ Mean pre-postpartum Hb decrease (units) 
▪ Rate of blood transfusion (%) 
▪ Adherence to intervention/ feasibility (%) 
▪ Rate of no to minor discomfort upon administration (acceptability)among 
participants 
▪ Rate of no to minor discomfort upon administration (acceptability) among providers  
▪ Rate of thromboembolic events up to 6 weeks postpartum (%) 
 
 
3.5 Recruitment and Enrollment 
RCT PICO 
P Women ≥18 years old, planned for vaginal delivery at Södersjukhuset, Stockholm Skåne    
University Hospital, Lund, Hudiksvall Hospital, Hudiksvall, Mowbray Maternity 
Hospital, and  Khayelitsha District Hospital during the period March 2023 to December 
2025  (n=1000). 
I 
Two grams (20ml) oral TA at full cervical dilation (n=500) 
C 20 ml oral, non-distinguishable, placebo at full cervical dilation (n=500) 
O Rate of PPH (≥ 500ml) between groups 
Hemorrhage in ml, estimated by weight  

 
 
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We will recruit women during a routine or planned antenatal visit after 35 gestational 
weeks, or after admission to the delivery ward before onset of labor. Potential 
participants will be approached and invited to partake in a non-committal brief 
information and screening regarding the study. If they are willing to participate and 
eligible, they will be included in the study after an informed consent process. 
3.6 Randomization 
Randomization will occur after a woman has been admitted to the labor ward. 
Participants will be randomized to receive either 20 ml of TA or 20ml of a placebo 
solution, equivalent to the IMP in appearance and taste. 
The randomization sequence will be computer-generated by KTA (Karolinska Clinical 
Trial Alliance). Randomization will be 1:1 in permuted blocks of 10 to allow for block-
sized deliveries to study sites. The placebo, an oral solution identical in appearance, taste, 
and volume to TA, will be developed and manufactured by Apotek Produktion och 
Laboratorier (APL) who will also supply the IMP. APL will perform the packaging, 
blinding, and marking of the IMP and placebo according to the randomization sequence 
sent them by KTA. The manufacturer and batch number of the drug administered for 
each participant will be recorded separately. All study sites will have a number to call in 
case unblinding is warranted. The sequence will be longer than 1000 to allow for 
differential rates of recruitment at the different study sites but recruitment will stop after 
the 1000th participant is included. The IMP/placebo flasks will delivered from APL to a 
central pharmacy location (Uppsala) and delivered in batches to each study site in 
Sweden. The IMP/placebo flasks for South Africa will be delivered in a temperature-
validated transport by World Courier to Mowbray Maternity Hospital pharmacy in South 
Africa and from there delivered in blocks of 10 to Khayelitsha District Hospital 
Pharmacy. Participants, clinical staff, and the researchers themselves, will be blinded as 
to which treatment the woman receives. The study product is stable at room temperature.  
Randomization will occur by taking the next sequential flask of IMP/placebo and noting 
its number on the IMP log. In Sweden this will be performed by study-trained midwives. 
In South Africa, randomization and dosage and tracking of the IMP will be performed by 
a certified and GCP-certified pharmacist at each study site. The pharmacist may also 
“block-randomize” in advance, allowing for enrolment after the pharmacy has closed for 

 
 
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the day. A research assistant will bring the IMP to the study participant. After use, the 
IMP flasks will be returned to the pharmacy (South Africa) or to the delivery ward 
medicine room (Sweden),  logged in the IMP log by the pharmacist or participating 
researcher, and stored until they have been monitored by the study monitor. All study 
procedures except those that form part of standard of care will be performed by GCP 
certified researchers or GCP certified delegated clinical staff. 
 
3.7 Study Procedures  
All study specific procedures will be performed by GCP certified study staff, or GCP 
certified clinical staff, that have been delegated these procedures by means of a 
delegation log, this includes the informed consent procedure, randomization and tracking 
the IMP, the administration of the IMP, and extraction of study data from medical 
records.  
The intervention is intake of 20 ml IMP/placebo. The oral solution is stable at room 
temperature and can be placed on a table next to the participant. When between 2 and 3 
hours of labor remains, the participant drinks the cup of 20ml liquid.  
Participants will experience three study procedures that form part of (routine) standard of 
care which will be performed by clinical midwives. 
1) A blood sample (hemoglobin, EVF, MCV, MCH, MCHC, LPC, TPC) in Sweden 
and hemoglobin only in South Africa,  taken upon admission . 
2) Measurement of blood loss volume weighing (1g=1ml) or calibrated drapes  
3) A blood sample including (hemoglobin, EVF, MCV, MCH, MCHC, LPC, TPC) 
in Sweden, and hemoglobin only in South Africa, taken after 24 hours (or prior to 
discharge should discharge occur before 24 hours). 
All study procedures including the measurement of the main outcome and most 
secondary outcomes will take place during the time the participant is admitted to the 
labor or postnatal ward. 
4. Data Collection Methods and monitoring 

 
 
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4.1 Measurement of outcomes 
Our main outcome is PPH>500ml assessed both by weight and by pre to post Hb 
difference. Blood loss is difficult to measure and correlation between weight-assessed 
assessment and pre-postpartum Hb difference is relatively poor (17, 18). PPH is 
defined as blood loss ≥500ml by the WHO and is the primary outcome used in most 
studies on TA. For this reason, we use PPH ≥500ml as out main outcome but include 
two measurements of its occurrence. Weight assessed rate of PPH will be measured by 
weighing all blood- and blood-soaked linen/pads within 2 hours of delivery according 
to clinical routines in Sweden as well as newly implemented routines in South Africa as 
part of the E-Motive Trial (19). Subsequent bleeding, if beyond the ordinary, within 24 
hours of delivery will be weighed and recorded by the midwife at the postpartum care 
ward and entered into clinical records as per routine care. Pre- postpartum Hb 
difference (g/L) will be measured by subtracting the Hb level taken 24 hours after 
delivery to that taken upon admission to the hospital, before onset of labor. A volume 
of 500ml represents ≈ 9% of a pregnant woman´s total blood volume. Assuming a mean 
Hb level of 114 in the third trimester, and an initial linear decrease in Hb, we stipulate 
that a ≥10 unit drop of Hb approximates the loss of 500ml of blood (20). Sweden 
diagnoses PPH only in cases of blood loss ≥1000ml (severe PPH) and there is an 
increasing consensus that this cut-off better correlates to clinical morbidity. We include 
rate of severe weight-assessed PPH, rate of blood transfusion, and mean weight-
assessed blood loss as secondary endpoints measuring bleeding after delivery. 
 
Hb will be measured in a blood sample taken at arrival to the delivery ward, 
hemoglobin level will be controlled 24 hours postpartum or directly before discharge if 
this occurs sooner. Biochemical analysis data will be extracted from digital or paper 
clinical records. Blood loss during delivery and up until two hours postpartum will be 
measured by weighing and recorded by the midwife in the delivery unit. Blood 
transfusions occurring within 24 hours, as well as thromboembolic events occurring 
within 6 weeks, will be extracted from clinical records.  Time of IMP/placebo 
administration in relation to labor/delivery, suspected side-effects of the medication, as 
well as any difficulty taking the medication (adherence) will be recorded by the midwife 

 
 
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on study case report forms. Data pertaining to primary and secondary endpoints will be 
retrieved from participant clinical records, digital laboratory report, or study case report 
forms and recorded to study electronic case report forms (eCRFs) in RedCap. Data will 
be collected and entered into the database by either one of the investigators or 
experienced research assistants. In South Africa, the 6 week outcome rate of 
thromboembolism will be recorded by telephone follow-up. 
4.2 Appropriateness of Intervention 
The effect of prophylactic oral TA during labor has not been studied. Our intervention is a 
2g stat dose of TA. Prophylactic oral treatment in pregnant woman is complicated as 
pharmacokinetics may be altered by physiological changes during pregnancy such as an 
increase in both plasma volume and renal clearance and by the fact that gastric emptying 
and gastrointestinal motility is decreased during labor, as well as by the unpredictable 
duration of labor.  
Several trials on prophylactic intravenous treatment of PPH have used a 1g dose (8,9). A 
treatment study on PPH (500-800ml) tested intravenous doses of 4g (loading dose) plus 6g 
over 6 hours without adverse events (4). A recent RCT on non-pregnant volunteers 
suggest that the bioavailability of oral TA could be as low as 47% (22).  Shakur-Still et al 
studied the pharmacokinetics of 4g of orally administered TA to pregnant women prior to 
planned cesarean delivery showing uptake similar to non-pregnant women taking about 
one hour to reach therapeutic serum concentration levels (13) whilst Muhunthan et al 
showed that mean time to maximum serum concentration  of 10 mg/L in women 
receiving 2 g of oral TA one hour postpartum was 2,9 hours (1). This assessment is 
preliminarily supported by our pilot study on 40 laboring women showing uptake of 2 g 
of TA to therapeutic levels over 2-4 hours (unpublished data).   
We therefore assess that a 2 gram dose is adequate for the oral form of TA in this study.  
The study protocol adheres closely to clinical practice. No additional staff is provided by 
the study to ensure that the allocated treatment is given. This is to ensure that the 
feasibility of routine administration of TA can be assessed both from a provider and a 
participant perspective. Feasibility is not expected to differ between study groups and is 

 
 
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defined as the overall proportion of women successfully receiving and swallowing their 
allocated treatment at the timepoint planned in the study protocol. 
TA is a well-tested product, available over the counter in Sweden, though not in South 
Africa, with mild and transient side-effects and no known increased risk of 
thromboembolic events (TE). Theoretically however the mechanism of action of TA 
could increase the risk of thromboembolism. Since the study tests the use of TA for a 
new indication (routine administration as a prophylaxis for PPH) we include the rate of 
TE as a secondary safety-related endpoint. Given an estimated baseline rate of TE in 
pregnancy of 1:1000, unchanged by the administration of TA, the expected rate of TE in 
both groups is 0-1 (21). 
4.3 Measurement of background variables 
Background-, pregnancy- and delivery- related variables will be retrospectively 
extracted from participant electronic or clinical records and entered into study 
electronic case report forms (eCRFs) by the investigator or research assistants. We will 
extract the following background and delivery-related variables from patient records:  
 
Background variables: 
▪ age at delivery 
▪ BMI at start of pregnancy 
▪ smoking 
▪ reproductive history 
▪ intercurrent diseases 
▪ Pregnancy related diseases 
 
Delivery data: 
▪ gestational age 
▪ fetal weight 
▪ placental weight (if available) 
▪ Apgar score 
▪ Umbilical cord pH (if available) 

 
 
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4.4 Data analysis 
Background, pregnancy, and delivery variables will be compared to demonstrate 
successful randomization using Fischer exact or Chi-square tests. Background data 
will be presented using a combination of the methods, as appropriate. Blood loss (ml) 
will be transformed to its natural logarithm to normalize the 
lognormal distribution and the geometric means corresponding to different groups will 
be compared using Student’s T-test on the transformed (normal) variable. PPH 
≥1000ml will be analysed using Chi2 test or Fisher’s exact test. Spearman’s rho is 
planned for correlation assessments. Feasibility and safety outcomes will be presented 
descriptively as incidence rates per group. A p-value <0.05 or 95% confidence 
interval encompassing 1 will be considered significant. 
Study groups will primarily be compared according to intention to treat (ITT) and 
secondarily per protocol (PP). The heterogeneity of study sites will be adjusted for in 
the final analysis. We plan a sub analysis per study site, per country as well as on the 
subgroup of women with prior history of severe PPH ≥ 1000ml, and women with 
anemia. 
4.4.1 Sample size calculation 
The baseline incidence of PPH≥ 500ml at the main recruiting site (Södersjukhuset, 
Sweden) is 39%. We assess that the smallest difference in treatment effect between 
TA and placebo groups would be an absolute decrease in PPH≥ 500ml of 9% (from 
39% to 30%, relative treatment effect 23%). Using a 2- group Chi2 test and 2-sided 
significance level we would require a sample size of 437 in each group to have 80% 
power to detect this decrease, or an equivalent decrease in rate of pre- postpartum Hb 
difference ≥ 10 units, with 95% confidence (from 39% to 30%). Based on baseline 
rates we assume that 8% of participants will be discontinued after randomization due 
to emergency caesarean section, and 1% of women will discontinue participation for 
other reasons. Our main outcomes are collected within 24 hours which will minimize 
loss to follow up. Accounting for this, we plan to randomize 500 women in each 
group, 1000 women in total. 
This sample size will give us 80% power to detect an absolute decrease in severe PPH 

 
 
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(≥ 1000ml) of 5% assuming a baseline rate of 10.2%, and a 4% decrease in blood 
transfusion assuming baseline rate of 7%, using a 2-group Chi2 test and 2-sided 
significance level, and a 3 unit difference pre-postpartum Hb (assuming a background 
Hb-difference of -8.9 gr/L and a standard deviation [SD] of 17gr/L) (23) using 
Student’s t-test. 
 
4.4.2 Handling of Dropouts or Missing Data 
 
We expect low rates of missing data because all interventions and measurements are 
performed during the in-hospital period. Some women are expected to be discontinued 
because they will require an emergency cesarean section after randomization. Analysis 
will be performed both according to ITT and PP. 
 
4.5 Research team qualifications and selection of study sites 
The collaboration is based on local research capacity at five clinical study sites.  
The study sites have been selected so as to include both primary and secondary level 
obstetric care. We have also selected units which have a focus on vaginal delivery and 
where the clinic staff are accustomed to, or motivated to learn, the standardized way in 
which blood loss is assessed in the study.  
  
The principal investigator Margit Endler, MD PhD is a senior consultant at 
Södersjukhuset and an associate professor at Karolinska Institutet, Department of Women 
and Children´s Health and adjunct senior lecturer at the University of Cape Town. She is 
HPCSA certified. She has been principal investigator on two RCTs, both in South Africa. 
She has a PhD on the epidemiology and pathophysiology of retained placenta and 
postpartum hemorrhage. She will be principal investigator to the study and provide the 
scientific and medical management of study procedures.  
Co-investigator and associate professor Pelle Lindqvist, MD PhD is a senior consultant 
and researcher at Södersjukhuset and is part of the collaborative Nordic Obstetric 

 
 
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Surveillance Study Group (NOSS) on placenta accreta spectrum disorders. He has an 
existing network at the Swedish study sites on the topic of postpartum hemorrhage.  
Co-investigator Gita Strindfors, M.D, is a senior consultant in obstetrics at 
Södersjukhuset and a doctoral student. She is a member of the IS-PAS (International 
Society of Placenta Accreta Spectrum) and has worked clinically with this group of 
patients for the past five years. She will project manage the study as part of her PhD 
education.  
Co-investigator Lars Thurn, MD PhD is a senior consultant and researcher at Lund´s 
University Hospital with a PhD on the topic of placenta accreta and postpartum 
hemorrhage. He will lead and coordinate the Lund study site.  
Co-investigator Zoltan Zavaczki, MD PhD is head of the department of obstetrics at 
Hudiksvall hospital and twenty years of clinical experience. He will lead and coordinate 
the Hudiksvall study site.  
Co-investigator Chantal Stewart MD is head of department at Mowbray Maternity 
Hospital (MMH)l in Cape Town Department and a specialist in high-risk pregnancy. She 
will lead and coordinate Mowbray study sites, MMH has approximately 12 000 deliveries 
per year. 
Co-investigator Christine Els MD is head of the obstetric department at Khayelitsha 
District Hospital. The hospital has 3000 deliveries per year.  
Co-Principal investigator for South Africa is Professor Justus Hofmeyr, MD PhD is a 
consultant gynecologist and obstetrician at the East London Hospital Complex, East 
London and a highly recognized expert in obstetrics. He has published 50 Cochrane 
systematic reviews and is an experienced lead researcher in the field of postpartum 
hemorrhage and other high risk obstetric disorders. He will act as consultant to the trial as 
a whole.  
All research collaborators as well as research assistants will be GCP certified and receive 
GCP refresher courses if necessary.  
4.6 Data Safety and Monitoring Plan 
 
Adverse events (AEs) and serious adverse events (SAEs) will be continuously 
monitored during the trial. The research team will employ a professional monitor that 

 
 
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will assess whether any unexpected rate of adverse events or discrepancy between 
treatment effects are grounds for an early closure of the study. The monitor will á 
priori assess trial and data safety based on the protocol before initiation.  
 
4.6.1 Display of Adverse Events 
 
All adverse events occurring during after initiation of study treatments during the 
study period, irrespective of a relation with the study drug/device will be monitored 
and displayed in summary tables according to The International Council for 
Harmonization of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) guidelines. 
Concurrent diseases that are reported at the time of inclusion will not be considered as 
adverse events, however any changes in symptoms or severity will be reported as an 
adverse even 
i. Analysis of Adverse Events 
 
Adverse events will be divided in severity categories and causality categories as listed 
below. 
 
• Mild = the subject is aware of the event, but the event is easily tolerated 
 
• Moderate = the subject experiences sufficient discomfort and the 
symptoms affect daily activities 
• Severe = the subject experience significant impairment of functioning 
and the symptoms substantially affect daily activities 
We draw a distinction between serious and severe AEs. The term severe is used to 
describe the intensity of the event but does not cause any of the serious effects of 
SAEs described below. 
 

 
 
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Further, the following definitions will be used to estimate the relation with adverse 
event and the IMP: 
 
• Probable = clinically/biologically highly plausible and there is a plausible time 
sequence between the onset of the AE and the administration of the study drug. 
There is sufficient documentation to suspect a causal relationship 
• 
Possible = clinically/biologically plausible and the relation cannot be rejected 
 
• 
Unlikely = a causal relation is improbable, and another explanation is more 
likely 
 
• 
Not possible to evaluate = relationship can be neither confirmed nor ruled out 
 
The severity and causality categories will be displayed and listed in a fashion which 
enables comparison between the different treatment groups. We will also note 
whether there are signs of regional or background differences in experienced adverse 
effects. As we are examining the effect of one single dose, we don´t expect to be able 
to evaluate dose-response relationship. 
4.6.3 Deaths, other serious adverse events (SAEs) and other significant adverse events 
Death or other serious adverse events will be defined according to The ICH Guideline on 
Clinical Safety Data Management, Definitions and Standards for Expedited Reporting as: 
“Any untoward medical occurrence that at any dose: results in death, is life-threatening, 
requires in-patient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, or is a congenital anomaly/birth defect”. 
Serious Adverse Events (SAEs) will include all serious events independent of whether 
they have a suspected causal relationship to the IMP or not. 
These will be listed separately and presented in summary tables and analyzed case by 
case. There will also be a separate objective individual event analysis in accordance with 
local clinical routine. 

 
 
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4.6.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Identification of and expedited reporting of SUSAR based on the RSI will be managed 
by the sponsor on regular basis. 
4.6.5 Reporting of AEs, SAEs and SUSARs 
 
 
Adverse Events (AEs) 
• All adverse events the participant experiences (excluding known side-effect 
at expected severity) will be documented on the participant’s paper case 
report file (CRF) following the participant by the midwife or doctor in 
charge during the delivery. The paper file will be collected by the principal 
study site investigator and transferred to the electronic participant CRF. 
• Adverse events will be reported irrespective if the event has any relation 
with the study drug or not. 
• Adverse events will be recorded in a separate CRF in the electronic study 
database RedCap and will define the suspected relationship to study 
medication, severity and expected outcome. 
• AEs will be registered until the end of the study. 
 
Serious Adverse Events (SAE) 
• All SAEs that occur during the study will be reported to the sponsor on a 
separate SAE report form within 24 hours of the initial notification of the 
event. The initial notification to the sponsor will be made on a SAE-report 
form, by e-mail or telephone. 
• At the time of initial reporting the investigator will provide the participant 
number, the personal number (Sweden) or patient record identification number 
(South Africa), birth date, description of the SAE and a preliminary 
assessment of causality. 
• Supplemental information will be reported by the investigator to the sponsor 

 
 
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as soon as possible. If the SAE is fatal or life-threatening the investigator will 
report back with follow-up information to the sponsor within 5 days after the 
initial report 
• If a reported SAE is present or ongoing when the participant completes the 
study the event will be followed for up to three months past the final visit or 
followed until final outcome is known or the condition is stable 
• If the participant has a prolonged hospital stay or is re-hospitalized due to 
conditions related to the neonate (delayed breastfeeding, neonatal jaundice, 
weight decrease, or other condition) this will not be reported as an SAE  
         SUSARs 
The sponsor will commit to reporting: 
 
• Any SUSAR of the study drug which is life threatening or fatal will be 
reported to the South African Health Products Regulatory Authority 
(SAPHRA) as soon as possible and not later than 7 days after the responsible 
investigator has been aware of the event. The report will be sent to SAPHRA 
and the relevant Ethics Committee  (HREC). Relevant follow-up information 
of the report will be sent within an additional 8 days (maximum of 15 days 
from initial report). 
• A SUSAR of the study drug/device that is not life threatening or fatal 
should be reported as soon as possible but within a maximum of 15 days to 
SAPHRA and the HREC. 
• All SUSARs will be reported to the SAPHRA on a Council for International 
Organizations of Medical Sciences (CIOMS)-form and also reported into the 
Eudra Vigilance Clinical Trial Module. 
During the study, the sponsor will report all SAEs with a suspected relation to 
the study drug, and SUSAR, to the SAPHRA and HREC once a year. Moreover, 
a safety report concerning the participants included in the study should be 

 
 
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supplied together with a summary on a risk/benefit evaluation for the 
participants in the study. The sponsor will also inform all investigators about 
occurring SUSARs during the study period. 
4.6.6 Unblinding 
In case of serious adverse events the blinding will be broken to identify the 
medication given in the trial. In cases of severe postpartum hemorrhage non-
respondent to uterotonic medication, 2 gram of TA (100mg/ml) is often given 
intravenously (administered at 1 ml/min) according to postpartum hemorrhage 
treatment guidelines and may be repeated once if bleeding continues after 30 
minutes or restarts within 24 hours . This dose may also be administered for 
study participants if needed, without breaking the blinding. Assuming the 
participants received a maximum of 2g in the study this would result in a total 
dose of 4g over the course of several hours which is still below the high dose 
treatment used in other clinical settings (22). If doses beyond this are needed, the 
blinding will be broken to avoid the risk of overdose. The randomization 
sequence linking each participant to the product received will be stored in a 
locked cabinet at a central site (Södersjukhuset in Sweden, and Mowbray 
Maternity, South Africa) who operate on a 24hr basis. A number will be posted 
at the nurse´s station of each study site, as well as in the investigational binder 
located at each site, in case unblinding is necessary. The following reasons are 
pre-stipulated for unblinding:  
 
• A severe adverse allergic reaction where the study medication received is 
believed to be the cause 
• Ongoing postpartum hemorrhage where an additional 2 g of TA has been given 
but additional doses are indicated within 6 hours of study dose. 
 
4.6.7 Stopping criteria 
 
We will not a priori perform an interim analysis with unblinding of the data to assess 

 
 
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early closure of the trial. We do not expect the IMP to have a magnitude of effect such 
that it would be evident in a smaller sample size population than the one planned and that 
would warrant early closure of the study. We further have no reason to suspect a negative 
effect related to the IMP that would warrant stopping of the study for safety reasons.  
Based on the long experience of using TA in clinical practice, and low rate of side 
effects, we do not expect new side effects or SAE associated to the IMP above the 
baseline incidence. We will monitor AEs and SAEs continuously. If SUSARS related 
to the medication occur repeatedly, or if SAEs occur at a rate higher than expected, the 
trial will be paused and we will ask the monitor to perform an unblinding and interim 
analysis of the data. If the SAEs are disproportionately related to the intervention arm, 
we will ask the monitor for advice on stopping the trial. 
4.6.8  Study monitoring 
We have appointed a monitor (KTA in Sweden and Marietjie Pretorius, UCT, in 
South Africa) that will ensure that the study is carried out according to the protocol 
and that data is collected, documented, and reported according to ICH-GCP and 
applicable ethical and regulatory requirements. Monitoring is performed as per the 
study’s monitoring plan and is intended to ensure that the subject’s rights, safety, and 
well-being are met as well as that data in the electronic database are complete, 
correct, and consistent with the source data. 
The sponsor will be responsible for securing agreement from all involved parties to 
ensure direct access to all trial related sites, source data and documents, and reports 
for the purpose of monitoring and auditing, and inspection by domestic and foreign 
regulatory authorities. The sponsor has also ensured that this is specified in the 
protocol as done above. 
 
Each site will have a Site Initiation Visit by the assistant coordinating investigator to 
ensure the site is ready for study start, that appropriate documentation is in place, that 
the site competence is sufficient, and that source data is defined. 
4.7 Data confidentiality 

 
 
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When women are randomized to the study, they will be automatically assigned a study 
ID by the Redcap data system. No identifying characteristics such as their name, 
address, telephone or unique personal identification number will be entered into the 
research database. All data from the study forms and participant records collected during 
the study will be registered in an pseudonymized form where participants are identified 
only by their study identification number. Paper forms will be stored in a locked 
cupboard at the university for the duration of the study period and then destroyed. 
 
Data will be handled and saved in such a way that no one but the researchers involved 
has access to them. Data will be saved for 10 years. The log containing the link between 
the participant’s personal data and study-ID will be protected by a code-key stored on a 
research specified computer to which only the main responsible researchers have access. 
Anonymized study data will be shared between the collaborating institutions University 
of Cape Town, Karolinska Institutet, Sweden, and Södersjukhuset (South General 
Hospital), Sweden. A collaboration agreement has been signed and certified between 
these three parties as well as a joint controller agreement regarding data transfer and 
analysis. Only pseudonymised data will be shared between institutions.   
 
5. Description of Risks and Benefits 
 
5.1 Potential risks and discomforts 
The study procedures include taking two venous blood samples. Venous blood samples 
are often routinely taken during delivery or postpartum and involve minor discomfort and 
minimal risk of complications such as irritation or local inflammation at the site of the 
sampling. The  
The safety profile of the IMP TA is described below. Every intake of a medicine not 
previously tried before involves the risk of an adverse reaction but it is in the case of TA 
assessed as very small. 

 
 
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5.2 Risk classification 
This is a phase IV trial in Sweden and Phase III in Southh Africa because we are using an 
unregistered administration form of TA. The medicinal product is however not new and 
not used in a new population or a new context but is used in a way that is not yet standard 
of care, i.e. as a routine prophylactic treatment for all women instead of select women. 
We are also using a mode of administration (oral solution) that is not currently used. The 
rationale is that most PPH occur in women without previous risk factors (7). Oral 
solution is described as equivalent in dose-efficacy to tablets or effervescent tablets (24). 
We estimate the risk entailed in the study however as greater than minimal simply 
because it involves (in the case of participants randomized to the IMP) intake of a 
medical product. The IMP, TA was developed in 1962 and has been used to treat bleeding 
since the late 1960´s. Oral TA, is available without prescription at pharmacies at a 
recommended dose of 1-1.5g three times daily. It´s safety profile for women during 
pregnancy is well-tested and as intravenous solution it is routinely used therapeutically, 
and prophylactically for high-risk women,  in pregnancy and postpartum with very low to 
unknown frequency of serious side effects.  
According to the Swedish Medicinal Information Service (FASS) and the Food and Drug 
Administration, common side effects constitute mainly of gastrointestinal problems such 
as nausea, vomiting, diarrhea, and abdominal pains but also headache and dizziness 
(between 1 and 10%). Less common side effects are transient allergic skin reactions 
(between 0.1% and 1 %). Rare side effects are impaired color perception and photopsia 
(between 0.01% and 0.1%) and extremely rare (so rare that the frequency cannot be 
calculated with current data) are thromboembolic events and seizures (24-26). A recent 
systematic review and Meta-Analysis concluded that TA, in addition to being effective in 
reducing PPH has an increased risk of causing minor side effects such as nausea and 
vomiting but does not seem to increase the risk of dizziness and photopsia (25) All 
research to date has shown that TA when used as prophylaxis or treatment for PPH in 
pregnant and puerperal women is not associated with an increased risk of thrombosis. 
The WOMAN trial (2017), a large RCT where 20 000 pregnant women were randomized 
to receiving TA or placebo as treatment for PPH, showed that there was no significant 

 
 
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difference between the groups regarding incidence of venous or arterial thromboembolic 
events (8). This was confirmed in the TRAAP-study (2018), where 4079 pregnant women 
received TA or placebo prophylactically immediately after the delivery of the child, no 
significant differences were seen regarding incidence of thromboembolic events (9). 
These studies confirm what has previously been reported for trauma patients (15). It is 
likely that there is a relationship between dose and adverse effects as most studies use a 
low dose regimen (1 g TA iv as loading dose and repeat dose of 1 g as slow infusion if 
continued hemorrhaging) but even when using high-dose regimen (loading dose 4 g over 
1 hour, then infusion of 1 g/hour over 6 hours) as in the EXADELI-study there were no 
significant differences in the incidence of severe adverse reactions (SARs) (22). There is 
no reported increased risk of fetal malformations (24-26). 
TA is listed on the World Health Organization´s List of Essential Medicines for the 
indication of treatment of postpartum hemorrhage (27). 
Table 1. Frequency of undesirable effects at a dose of 4 g/day (MedDRA LLT): 
 
Organ Class 
Frequency 
Common 
Uncommon 
Not known 
Adverse Reactions(ARs) 
Serious Adverse 
Reactions (SARs) 
Nervous system 
disorders 
Dizziness, Headache 
Convulsions 
Gastrointestinal 
Disorders 
Vomiting, Diarrhea, 
Nausea, Abdominal 
pain 
Skin and 
subcutaneous tissue 
disorders 
Allergic skin 
reaction 
Eye disorder 
Impaired color 
vision and other 

 
 
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visual disturbances 
Vascular disorders 
Thromboembolic 
events 
 
5.3 Minimizing risk 
 
The study procedures themselves- intake of 20ml of TA and two blood samples are 
not expected to cause more than minor discomfort or risk and both interventions often 
occur as part of routine care for women in delivery. As Reference Safety Information 
(RSI), we will provide a detailed overview of the safety profile of the IMP (TA) to all 
investigators including the expected ARs and SARs listed in the Summary of Product 
Characteristics (SmPC) as detailed in the table below. 
It will serve as the basis for expectedness assessments of ‘suspected’ SARs by the 
sponsor for expedited reporting of suspected unexpected serious adverse reactions 
(SUSARs) and annual safety reporting. SAR being “all noxious and unintended 
responses to an investigational medicinal product related to any dose administered 
that at any dose results in death, is life- threatening, requires hospitalization or 
prolongation of existing hospitalization, results in persistent or significant disability or 
incapacity, or is a congenital anomaly or birth defect”. This may imply a reasonable 
possibility of a causal relationship between the event and the IMP, i.e., evidence to 
suggest a causal relationship. 
This section will be regularly assessed and revised if the risk/benefit relationship of the 
therapeutic effect of TA to ARs/SARs should change. 
5.4 Potential benefits 
 
For participants receiving the IMP, participation may result in less PPH. The long-term 
aim of this project is to optimize intrapartum management of PPH in an effort to reduce 
morbidity. Reducing complications to PPH will reduce the need of hysterectomy, blood 
transfusion, and medication, length of hospital stay, sick leave, psychological sequelae 

 
 
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and medical costs. It would also benefit the new-born, reducing acute morbidity at birth 
and separation from the mother, and increasing immediate uptake of breastfeeding. 
Should prophylactic oral TA prove to be effective in preventing PPH, it could be a 
critical treatment in both high and low resource settings due to its low cost, stability 
and easy administration. If orally administered TA proves equally efficient to 
intravenous TA in reducing blood loss postpartum this should be considered for 
inclusion in routine delivery care. By including low resource settings in other countries 
in the larger RCT we hope to help increase optimal management of vaginal birth in 
these and other countries. In low-income countries many women are anemic even 
before pregnancy due to malnutrition and concurrent diseases such as malaria, HIV and 
tuberculosis, it is therefore of utmost importance to prevent unnecessary bleeding 
during delivery. Oral TA compared to intravenous TA is widely available, easy to 
administer even by the woman herself, cheap, and stable at room temperature. 
Strengthening research capacity in the participating study sites in both Sweden and South 
Africa is a peripheral but important benefit and many clinical staff will gain both 
theoretical (through GCP certification) and practical research competence.  
 
5.5 Alternatives to participation 
The alternative to participation in the study is standard delivery care. The quality of care 
received during labor or afterwards will not be affected by participation or non-
participation. Individuals that chose not to participate will be assured that this will not 
affect their clinical care whilst in the hospital or afterwards.  
5.6 Harm: benefit ratio 
PPH is the leading cause of maternal death worldwide and entails both short- and 
long-term morbidity. TA is a well-tested product used to treat hemorrhage and heavy 
menstrual bleeding, has no known common severe side-effects, is routinely used to 
treat PPH, and is available over the counter in many settings. The purpose of clinical 
trial is to assess the effectiveness of its prophylactic use in women in labor. The risk-
benefit calculus therefore poses the question if the potential benefits outweigh the 

 
 
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cost, resources and expected side effects related to routine use. Our assessment is 
therefore that even a small prophylactic effect would outweigh the expected risk of 
the intervention. The aim of this project is to optimize intrapartum management to 
reduce PPH-related morbidity. Reducing complications to PPH will reduce the need 
of hysterectomy, blood transfusion, and medication, length of hospital stay, sick 
leave, psychological sequelae and medical costs. It would also benefit the newborn, 
reducing acute morbidity at birth and separation from the mother, and increasing 
immediate uptake of breastfeeding. 
 
Exploring alternative routes of TA administration for PPH reduction is a stated 
research priority by the WHO. In low-income countries many women are anemic even 
before pregnancy due to malnutrition and concurrent diseases such as malaria, HIV and 
tuberculosis, it is therefore of utmost importance to prevent unnecessary bleeding 
during delivery. Even a small clinical effect and reduction of bleeding can make a big 
difference for survival and recovery in poor countries where many women have 
hemoglobin values as low as 50 to 60 g/L and little margin exists to life-threatening 
anemia. 
 
Oral TA compared to intravenous TA is widely available, easy to administer even by 
the woman herself, cheap, and stable at room temperature. Intravenous TA is effective 
to treat and prevent PPH. Intravenous TA however may require refrigeration which is 
unrealistic in many clinical settings. Administration is done slowly and requires the 
insertion of a peripheral line which 1) requires the presence of a skilled provider, and 2) 
means that the provider cannot perform other crucial interventions such as uterine 
compression during the time it takes to insert the line. The cost of intravenous TA is a 
relative barrier to routine administration in high resource settings and an absolute 
barrier in low resource settings. One treatment dose (1-2g) intravenous TA costs at a 
minimum 46-92$, whereas 1-2g oral TA is available for as little as 1.6-3.2$ per 
treatment, an almost 30-fold price difference. 
Should prophylactic oral TA be effective in preventing PPH, it could be of critical 
impact in both high and low resource settings. Oral compared to intravenous TA is 

 
 
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applicable to all birth settings, including home births. If oral TA is feasible and has 
similar efficiency to intravenous TA in reducing PPH, it should be considered for 
inclusion in routine delivery care. 
6. Informed Consent  
6.1 Informed consent process 
Women will be included to the study after a private written informed consent procedure 
in a private space. The informed consent procedure will be led by research midwives, 
study investigators, or trained and experienced research assistants, all GCP certified. The 
ICF process will take place in the language of the participant´s choice limited to English, 
IsiXhosa and Afrikaans in the South African context. During this process women will be 
informed of the risks and benefits of the study and their rights as participants. Participants 
will be able to discuss participation with family, friends, or advisors before signing the 
consent form. 
 
The ICP will occur at a participating study site atwhich the women has sought care, either 
for an antenatal check-up, or after admission to the delivery ward for induction or in the 
latency phase. Women will be recruited before onset of active labor so as to ensure they 
can take part, understand and consent during the ICP.  
 
 
6.2 Capacity to consent and assessment of vulnerability 
The study will not include minors, adults with intellectual disability or mental illness 
interfering with decision making. All participants will be able to give informed consent to 
participation. The study will not exclude participants of low socioeconomic status, prior- 
or pregnancy related health disorders as these are groups for whom the intervention may 
be particularly valuable. The research will take place at clinical facilities to which the 
participants have been admitted for labor or which they are anyway consulting for 
antenatal check-ups. All primary research procedures will take place within 24 hours of 
admission.  

 
 
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6.3 Comprehension of information 
The ICP will be performed by two research assistants who are experienced in performing 
this role during clinical trials in the field of reproductive health in general. Their 
experience includes assessing participants ability to understand the content of the ICP by 
asking them to relay back what they have understood from the text.  The ICP will be 
performed in the participant´s native or preferred language.  The research assistant will at 
standardized points in the process pause to ascertain that the participant understands what 
is being read to her by having her summarize the main content in her own words.   
6.4 Withholding information 
Participants will be blinded to whether they received the IMP or the placebo but will be 
aware of the blinding. No other information regarding the study will be withheld from 
participants.  
6.5 Consent and assent forms 
The informed consent form will be available in Swedish for participants in Sweden, and 
translated into English, IsiXhosa and Afrikaans for participants in South Africa.  The 
content of the consent forms will comply with the legal and ethical requirements detailed 
in the Standard Operating Procedure relating to Informed Consent. 
 
 
6.6 Privacy and Confidentiality 
Forms for collection of data about participants will not include names or addresses, only 
the participant’s medical record number and her study ID number. Signed informed 
consent forms will record participants´ names and signatures only and will be filed 
separately from other study documents. Likewise, a locator form with the participant’s 
name, study ID, South African ID number, medical record numbers, address, and phone 
number, will be filed separately from all other study documentation. South African ID 
numbers will be needed to follow-up on medical records or unscheduled clinical visits 
after the delivery, in facility records. All study forms will be kept in a locked cabinet at 

 
 
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the research office at UCT and no one outside of the core research team members will 
have access to these forms. Study documents will be archived securely in a locked 
cupboard, accessible to the investigators only, for ten years, and then shredded. Staff 
involved in data entry will not have access to any identifying information on the 
participants or facilities. All electronic data files will be password-protected. We will not 
advertise the study at the clinics or surrounding communities.   
7. Reimbursement for Participation 
Women recruited to the study will receive compensation for the inconvenience and time 
loss that the study procedures are expected to incur. Participants in South Africa will be 
compensated R150 upon discharge from the hospital, in the form of a food voucher, in 
line with the 2022 SAPHRA participant compensation model 
https://www.sahpra.org.za/wp-content/uploads/2022/01/SAHPGL-CEM-CT-02_v2-
Guideline-for-CT-Participant-Time-Inconvenience-and-Expense-TIE-Compensation-
Model.pdf. Swedish participants are not expected to incur any loss of income due to 
study participation will not receive any compensation.  
8. Emergency Care and Insurance for Research-Related Injury 
 
The research is conducted within the normal delivery health care system in Sweden and 
South Africa and does not include any procedures outside of routine perinatal care. 
Patients in Sweden who suffer from injury are insured through the Swedish Patient 
Insurance (LÖF) and may be offered compensation determined by the Swedish Patient 
Injury Act. 
Patients in South Africa are covered by an no fault insurance policy to cover injuries 
incurred in research not sponsored by a pharmaceutical company.  
 
9. What Happens at the End of a Study? 
 
Oral tranexamic acid in tablet from which is assumed to be equivalent to the oral 
solution in dose-efficacy is available and part of routine treatment for PPH in 

 
 
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delivery wards. Because of its low cost, stability at room temperature it would be 
easily integrated into routine share should the treatment prove effective as a 
prophylactic treatment for PPH.  
The study is taking place in public facilities and as such we will work directly with the 
staff and management of the facility to build their capacity and obtain their input on the 
study implementation. They will also be informed of the study results, and the study team 
will work with the facility and policy makers to consider how the results may be 
implemented.  At the time of recruitment, we will inform participants when we anticipate 
having final results for the study, and we will encourage them to contact us at the contact 
numbers on the consent form so they can be informed about the study results if they wish 
to know them.  
Following analysis of study results, departmental heads provincial DOH structures will 
be invited to take part in the study findings with a view to initiating policy and program 
changes if supported by the study findings. We will ensure timely sharing and publication 
of results, and the data collected will ultimately be available for public use. Study 
findings will be made public through scientific meetings and peer-reviewed journals, as 
well as through a structured dissemination process with facility staff and policy makers.  
Other pre-stipulated end-of-trial measures are the following: 
 
• Within 90 days of completion of the study, the sponsor will report to the 
SAPHRA and the HREC that the study is completed as stated in the 
protocol. 
• 
If the study will be ended and closed prematurely, the sponsor will report to 
the SAPHRA and the HREC within 15 days. The reasons for the decision 
shall be reported 
• 
The EU-common form ”end of trial” shall be used and sent electronically to the 
SAPHRA 
• The sponsor will also send a summarizing report to the EudraCT database 
within 12 months after the study has been closed. 

 
 
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10. References 
 
1. 
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causes of maternal death: a WHO systematic analysis. The Lancet Global health. 
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2. 
Moodley, J., Fawcus, S. & Pattinson, R.C. 2020, '21 years of confidential 
enquiries into maternal deaths in South Africa : reflections on maternal death assessments', 
Obstetrics and Gynaecology Forum, vol. 30, no. 4, pp. 4-7. 
3. 
Fadel MG, Das S, Nesbitt A, Killicoat K, Gafson I, Lodhi W, et al. Maternal 
outcomes following massive obstetric haemorrhage in an inner-city maternity unit. Journal of 
obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology. 
2019;39(5):601-5. 
4. 
Ducloy-Bouthors AS, Jude B, Duhamel A, Broisin F, Huissoud C, Keita-
Meyer H, Mandelbrot L, Tillouche N, Fontaine S, Le Goueff F, Depret-Mosser S, Vallet B; 
EXADELI Study Group; Susen S. High-dose tranexamic acid reduces blood loss in 
postpartum haemorrhage. Crit Care. 2011;15(2):R117. 
5. 
Sentilhes L, Winer N, Azria E, Senat MV, Le Ray C, Vardon D, et al. 
Tranexamic Acid for the Prevention of Blood Loss after Vaginal Delivery. N Engl J Med. 
2018;379(8):731-42. 
6. 
Gilmandyar D, Thornburg LL. Surgical management of postpartum 
hemorrhage. Seminars in perinatology. 2019;43(1):27-34. 
7. 
Novikova N, Hofmeyr GJ, Cluver C. Tranexamic acid for preventing 
postpartum haemorrhage. The Cochrane database of systematic reviews. 
2015(6):Cd007872. 
8. 
WOMAN Trial Collaborators. Effect of early tranexamic acid administration 
on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage 
(WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet 
(London, England). 2017;389(10084):2105-16. 
9. 
Sentilhes L, Winer N, Azria E, Sénat MV, Le Ray C, Vardon D, Perrotin F, 
Desbrière R, Fuchs F, Kayem G, Ducarme G, Doret-Dion M, Huissoud C, Bohec C, 
Deruelle P, Darsonval A, Chrétien JM, Seco A, Daniel V, Deneux-Tharaux C; Groupe de 
Recherche en Obstétrique et Gynécologie. Tranexamic Acid for the Prevention of Blood 
Loss after Vaginal Delivery. N Engl J Med. 2018 Aug 
10. 
WHO recommendation on tranexamic acid for the treatment of 
postpartum haemorrhage. World Health Organization. 2017. 
11. 
Picetti R, Shakur-Still H, Medcalf RL, Standing JF, Roberts I. What 
concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of 
pharmacodynamics studies. Blood coagulation & fibrinolysis : an international journal in 
haemostasis and thrombosis. 2019;30(1):1-10. 
12. 
Sindet-Pedersen S. Distribution of Tranexamic Acid to Plasma and Saliva 
After Oral Administration and Mouth Rinsing: A Pharmacokinetic Study. The Journal of 

 
 
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Clinical Pharmacology. 1987;27(12). 
13. 
Shakur-Still H, Roberts I, Grassin-Delyle S, Chaudhri R, Geer A, Arribas M, 
Lamy E, Mansukhani R, Lubeya MK, Javaid K, Kayani A, Israr N, Mazhar SB, Urien S, 
Bouazza N, Foissac F, Prowse D, Carrington L, Barrow C, Onandia JG, Balogun E. 
Alternative routes for tranexamic acid treatment in obstetric bleeding (WOMAN-
PharmacoTXA trial): a randomised trial and pharmacological study in caesarean section 
births. BJOG. 2023 Apr 5. 
14. 
Muhunthan K, Balakumar S, Navaratnaraja TS, Premakrishna S, 
Arulkumaran S. Plasma Concentrations of Tranexamic Acid in Postpartum Women After 
Oral Administration. Obstet Gynecol. 2020 Apr;135(4):945-948.  
15. 
Roberts I, Shakur H, Coats T, Hunt B, Balogun E, Barnetson L, et al. The 
CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of 
tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding 
trauma patients. Health technology assessment (Winchester, England). 2013;17(10):1-79. 
16. 
McCormack PL. Tranexamic acid: a review of its use in the 
treatment of hyperfibrinolysis. Drugs. 2012;72(5):585-617. 
17. 
Bedson R, Riccoboni, A. Physiology of pregnancy: clinical anaesthetic 
implications. Continuing Education in Anaesthesia Critical Care and Pain. 
2014;14(2):69-72. 
18. 
Anger H, Durocher J, Dabash R, Winikoff B. How well do postpartum 
blood loss and common definitions of postpartum hemorrhage correlate with postpartum 
anemia and fall in hemoglobin? PLoS One. 2019;14(8):e0221216. doi: 
10.1371/journal.pone.. eCollection 2019. 
19. 
The E-Motive Trial. University of Birmingham. 
https://www.birmingham.ac.uk/research/bctu/trials/womens/emotive/e-motive.aspx 
20. 
Churchill D, Nair M, Stanworth SJ, Knight M. The change in haemoglobin 
concentration between the first and third trimesters of pregnancy: a population study. BMC 
pregnancy and childbirth. 2019;19(1):359. 
21. 
https://www.acog.org/clinical/clinical-guidance/practice-
bulletin/articles/2018/07/thromboembolism-in-pregnancy 
22. 
Grassin-Delyle S SM, Lamy E, Urien S, Runge I, Foissac F, Bouazza N, 
Treluyer JM, Arribas M, Roberts I, Shakur-Still H. Pharmacokinetics of tranexamic acid after 
intravenous, intramuscular, and oral routes: a prospective, randomised, crossover trial in 
healthy volunteers. Br J Anaesth. 2022 128(3):465-72. 
23. 
Lindqvist PG, Svensson PJ, Dahlbäck B, Marsál K. Factor V Q506 mutation 
(activated protein C resistance) associated with reduced intrapartum blood loss--a possible 
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FASS. Tranexamsyra. 
https://www.fass.se/LIF/result?query=tranexamic%20acid&userType=0 (Swedish) 
25. 
FDA. Tranexamic Acid N22-430S003 Clinpharm. PREA. 
https://www.fda.gov/media/86940/download 
26. 
Xia Y, Griffiths BB, Xue Q. Tranexamic acid for postpartum hemorrhage 
prevention in vaginal delivery: A meta-analysis. Medicine (Baltimore). 2020;99(3):e18792. 

 
 
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27. 
World Health Organization. List of Essential Medicines. 
https://list.essentialmeds.org/recommendations/909   
 
 

 
 
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11. List of Appendix Material 
The following appendix material is attached in addition to Sections A, B, and C,  
• Funding/ grant application 
•    Consent and assent forms (English versions) 
•    Budget summary