Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000176369p
Ethics application status
Submitted, not yet approved
Date submitted
23/01/2017
Date registered
2/02/2017
Date last updated
29/06/2021
Date data sharing statement initially provided
16/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Post partum haemorrhage (PPH) prevention: oxytocin pharmacokinetics and maternal body mass index (BMI).
Scientific title
Correlative assessment of prophylactic oxytocin pharmacokinetics (PK) to maternal body mass index (BMI) following intravenous (IV) and intramuscular (IM) administration, for the prevention of postpartum haemorrhage, at elective caesarean section. An open label, prospective, exploratory, randomised controlled trial.
Secondary ID [1] 290966 0
Nil Known
Universal Trial Number (UTN)
U1111-1191-7952
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Postpartum haemorrhage 301730 0
Overweight and obesity 301731 0
Condition category
Condition code
Reproductive Health and Childbirth 301426 301426 0 0
Other reproductive health and childbirth disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Oxytocin solution for injection
1) The dose administered: 10 International units (IU)
2) The duration of administration: a single injection to be administered following birth (within 1-2 minutes)
3) The mode of administration: Intramuscular (IM) injection
Intervention code [1] 296929 0
Treatment: Drugs
Intervention code [2] 296930 0
Prevention
Comparator / control treatment
Oxytocin solution for injection
1) The dose administered: 5 International units (IU)
2) The duration of administration: a single injection to be administered following birth (within 1-2 minutes)
3) The mode of administration: 'slow' bolus (1-2 minutes) intravenous (IV) injection
Control group
Active

Outcomes
Primary outcome [1] 300821 0
The primary outcome of the trial is to evaluate the relationship between maternal BMI and the pharmacokinetics (PK) of a single dose of oxytocin administered via either: a ‘slow bolus’ (1-2 minutes) intravenous (IV) injection or a intramuscular (IM) injection, to participants with a full term (equal to, or more than, 37 weeks gestation) singleton pregnancy at the time of elective caesarean section (no labour) or vaginal birth (labour).

Pharmacokinetic parameters include: Absolute bioavailability (F), absorption rate constant, (Ka), clearance (Cl) and volume of distribution (Vd). Bioanalysis and modelling will be used to determine maximum plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration-time curve (AUC) and terminal phase half-life (t 1/2).
Timepoint [1] 300821 0
Blood samples will be collected from participants for pharmacokinetic (PK) analysis: before birth (1 hour, or less) and then following birth, and timed from the commencement of oxytocin administration, at a 'desired' nine further targeted time points of: 3 (+/-0) minutes, 5 (+/-1) minutes, 10 (+/-2) minutes, 15 (+/-2) minutes, 20 (+/-2) minutes, 30 (+/-3) minutes, 60 (+/-5) minutes, 120 (+/- 5) minutes and 180 (+/-5) minutes.
Secondary outcome [1] 331076 0
None
Timepoint [1] 331076 0
None

Eligibility
Key inclusion criteria
1) A Body Mass Index (BMI) classified as either: normal range, (BMI 18.5-24.99 Kg/m2), overweight/pre-obese (BMI 25.00-29.99 Kg/m2), obese class I (BMI 30-34.99 Kg/m2) obese class II (BMI 35-39 Kg/m2) or obese class III (equal to, or more than, 40.00 Kg/m2), at booking
2) Singleton pregnancy
3) Live fetus
4) Full term pregnancy (equal to, or more than, 37 weeks)
5) Mode of birth: elective lower segment caesarean section (LUSCS) (no labour) or a vaginal birth (following labour)
6) Parity: 3, or less, at time of recruitment (antenatal)
7) Haemoglobin (Hb) equal to, or more than, 100g/L
8) 18-40 years of age
9) Capacity to provide written, informed consent.
Minimum age
18 Years
Maximum age
40 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1) A Body Mass Index (BMI) classified as either: underweight <18.5 Kg/m2, at booking
2) Prior to birth, where it is already known that there will be a clinical indication for the administration of Syntometrine ('Registered Trademark') and/or Ergometrine for the routine management of the third stage of labour
3) A diagnosis of Type I insulin dependent diabetes (IDDM)
4) General anaesthesia for caesarean section
5) A recipient of an intra-partum oxytocin intravenous infusion (IVI)
6) A requirement for an emergency caesarean section
7) <37 completed weeks of pregnancy
8) Previous hypersensitivity/adverse reaction to oxytocin (Syntocinon 'Registered Trademark') or any of the excipients in its formulation
9) Evidence of hepatic or renal dysfunction, demonstrated by abnormalities in pathology reports and/or documentation in hospital records
10) The presence of hypertension requiring IV therapy
11) Presence of maternal cardiac disease/arrhythmias, where a reduced dose of oxytocin maybe advocated
12) Unwillingness or inability to follow the procedures outlined in the Participant Information and Consent Form
13) Mentally, cognitively or legally incapacitated or unable to provide informed consent
14) Co-recruitment/participation in another clinical trial where there is pharmaceutical intervention
15) Documented, or declared, use of: methadone, buprenorphine and/or illegal drugs during pregnancy
16) Presence of (any/all): Hepatitis B Surface Antigen (HBsAg), positive Hepatitis C Antibody Test or Human Immunodeficiency Virus (HIV) Antibody
17) Known abnormality of placentation (e.g. placenta praevia, vasa praevia, placental abruption, placenta accreta/incretta/percreta).

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants will be assigned to the route of oxytocin administration by the use of sequentially numbered, opaque, sealed envelopes, pre-prepared by a party not involved in the conduct of the trial
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be assigned to the route of oxytocin administration by following a simple randomization procedure, rather like the ‘flip of a coin’.

Briefly, there will be six boxes representative of the six different study groups. Each box will contain twenty envelopes, one for each participant who has been allocated to that study group.

Prior to the commencement of the trial, for each of the six individual study groups, a person who has no involvement in the trial conduct, will put one randomization instruction into an opaque envelope and seal it. The twenty envelopes will then be ‘shuffled’ in order to mix them up. Thereafter, the envelopes will be sequentially numbered 1-20.

Ultimately, for each of the six study groups, this simple randomization process will generate instructions to randomize the n=20 participants within the study group to receive: either an intramuscular (IM) injection (n=10) or a 5 IU of oxytocin administered via a ‘slow’ (1-2 minutes) intravenous (IV) bolus injection (n=10).

In order to randomise the participant prior to birth, the researcher will take the next numbered envelope from the appropriate box belonging to the study group to which the participant has been allocated, and open it. Oxytocin will be administered to the participant as directed by the contents of the envelope that has been assigned to them.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/01/2023
Actual
Date of last participant enrolment
Anticipated
31/12/2025
Actual
Date of last data collection
Anticipated
1/01/2026
Actual
Sample size
Target
120
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 7356 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 7357 0
Jessie McPherson Private Hospital - Clayton
Recruitment postcode(s) [1] 15150 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 295396 0
University
Name [1] 295396 0
Monash University
Country [1] 295396 0
Australia
Funding source category [2] 295398 0
Commercial sector/Industry
Name [2] 295398 0
GlaxoSmithKline plc (United Kingdom)
Country [2] 295398 0
United Kingdom
Primary sponsor type
Hospital
Name
Monash Health
Address
246 Clayton Road
Clayton
Victoria 3168
Country
Australia
Secondary sponsor category [1] 294230 0
None
Name [1] 294230 0
Address [1] 294230 0
Country [1] 294230 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 296731 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 296731 0
Monash Health Research Directorate
Level 2, I Block
Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Ethics committee country [1] 296731 0
Australia
Date submitted for ethics approval [1] 296731 0
19/01/2017
Approval date [1] 296731 0
Ethics approval number [1] 296731 0

Summary
Brief summary
It has been reported that both the occurrence of primary postpartum haemorrhage (PPH) (birth to 24 hours postpartum) and rates of maternal overweight and obesity are increasing. For the ‘routine’ management of the third stage of labour and primary post partum haemorrhage prophylaxis, mothers are usually given the same dose of oxytocin without consideration of their weight or body mass index (BMI), which many other pharmaceutical products require. We propose that for those whose body mass index (BMI) would classify them as being either overweight/pre-obese (BMI 25.00-29.99 Kg/m2) or obese (BMI equal to, or more than, 30Kg/m2), that this ‘standard dose’ for all maybe insufficient to attain the therapeutic levels of oxytocin necessary to invoke uterine contractility, thereby predisposing this cohort of mothers to atonic PPH.

The research study is an investigator initiated, single centre (Monash Health), phase 4, open label, prospective, randomized controlled trial, to evaluate the relationship between participant (maternal) BMI and the pharmacokinetics (PK) of a single dose of oxytocin administered either as: a 'slow' bolus (1-2 minutes) intravenous (IV) injection or an intramuscular (IM) injection, given for primary postpartum haemorrhage prophylaxis following birth.

The trial seeks to collect blood samples from n=120 participants:

Those who are having an elective (no labour) caesarean section (n=100) under regional anaesthesia, and are representative of BMIs: normal range, (BMI 18.5-24.99 Kg/m2), overweight/pre-obese (BMI 25.00-29.99 Kg/m2), obese class I (BMI 30- 34.99 Kg/m2) obese class II (BMI 35-39 Kg/m2) or obese class III (equal to, or more than, 40.00 Kg/m2).

Those who are having a vaginal birth (n=20) and composed of only of those who have a BMI that is within the normal range (18.5-24.9 Kg/m2).

Ultimately, there will be n=20 participants in each of the six study groups. Of these, following randomisation, each study group, will be composed of n=10 participants who have received 5 IU of oxytocin via a ‘slow bolus’ (1-2 minutes) intravenous (IV) injection, and n=10 who have been given 10 IU oxytocin through an intramuscular (IM) injection.

Blood samples will be collected from participants for pharmacokinetic (PK) analysis: before birth (1 hour, or less) and then following birth, and timed from the commencement of oxytocin administration, at a 'desired' nine further targeted time points of: 3 (+/-0) minutes, 5 (+/-1) minutes, 10 (+/-2) minutes, 15 (+/-2) minutes, 20 (+/-2) minutes, 30 (+/-3) minutes, 60 (+/-5) minutes, 120 (+/-5) minutes and 180 (+/-5) minutes.

Pharmacokinetic parameters include: Absolute bioavailability (F), absorption rate constant, (Ka), clearance (Cl) and volume of distribution (Vd). Bioanalysis and modelling will be used to determine maximum plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration-time curve (AUC) and terminal phase half-life (t1/2).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 71858 0
Prof Euan M. Wallace
Address 71858 0
Department of Obstetrics and Gynaecology Monash University
Level 5, Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Country 71858 0
Australia
Phone 71858 0
+61 3 9594 5145
Fax 71858 0
+61 3 9594 5003
Email 71858 0
[email protected]
Contact person for public queries
Name 71859 0
Ms Joanne C. Mockler
Address 71859 0
Department of Obstetrics and Gynaecology Monash University
Level 5, Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Country 71859 0
Australia
Phone 71859 0
+61 3 8572 2840
Fax 71859 0
+61 3 9594 6811
Email 71859 0
[email protected]
Contact person for scientific queries
Name 71860 0
A/Prof Michelle McIntosh
Address 71860 0
Drug Delivery, Disposition and Dynamics
Faculty of Pharmacy and Pharmaceutical Sciences
Monash University
Level 2, Building 404, Parkville Campus
381 Royal Parade
Parkville
Victoria 3052
Country 71860 0
Australia
Phone 71860 0
+61 3 9903 9531
Fax 71860 0
Email 71860 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
The data will be shared through publication in a peer reviewed journal following completion of the trial.
When will data be available (start and end dates)?
We hope to have the final data set available from the middle of 2021 for analysis. Once the data analysis has been completed a manuscript will be prepared for submission to a peer reviewed journal.
We will provide a date for IPD availability when we are closer to commencing this trial, at this time, we do not have a definite date.
Available to whom?
1) The editors and peer reviewers of the final manuscript.
2) Interested parties who contact the senior author, requesting more information about the trial.
3) Those individuals who read the journal where the manuscript has been accepted for publication are able to see the de-identified, aggregated data.
Available for what types of analyses?
The raw data will not available for external analysis. Associated documents such as protocol, PI&CF may be available by contacting the senior author. The senior author will determine who has access to documentation and data associated with this trial.
How or where can data be obtained?
The data will be shared either through publication in a peer reviewed journal or by those parties who are interested, emailing the senior author directly to seek more information about the trial.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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