Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613001142729
Ethics application status
Approved
Date submitted
27/09/2013
Date registered
14/10/2013
Date last updated
28/06/2023
Date data sharing statement initially provided
28/06/2023
Date results information initially provided
28/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Omega-3 fats to reduce the incidence of prematurity: the ORIP trial
Scientific title
Omega-3 fats to reduce the incidence of prematurity in healthy women with a singleton or multiple pregnancy less than 20 weeks gestation
Secondary ID [1] 281834 0
Nil
Universal Trial Number (UTN)
Trial acronym
The ORIP trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Early preterm birth 288190 0
Condition category
Condition code
Diet and Nutrition 288554 288554 0 0
Other diet and nutrition disorders
Reproductive Health and Childbirth 290687 290687 0 0
Fetal medicine and complications of pregnancy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
3 capsules of fish oil containing a total dose of approximately 800 mg of DHA will be administered orally per day until 34 weeks gestation or birth (whichever occurs first). Women will be asked to return unused supplements at the end of the 34 weeks gestation when a spot blood sample is taken. The proportion of capsules returned will serve as a measure of adherence. DHA concentration at the end of intervention will be used as an independent biomarker of adherence.
Intervention code [1] 286392 0
Prevention
Comparator / control treatment
Vegetable oils with a trace of DHA to aid masking
Control group
Placebo

Outcomes
Primary outcome [1] 288811 0
Evaluate the impact of fish oil supplementation on the incidence of early preterm birth compared with placebo.
Timepoint [1] 288811 0
Early preterm birth defined as delivery before 34 weeks completed gestation age.
Secondary outcome [1] 301047 0
Incidence of post-term induction or post-term pre labour caesarean delivery via case note audit based on LMP and U/S report
Timepoint [1] 301047 0
at birth
Secondary outcome [2] 301048 0
Preterm birth (GA <37 completed weeks at birth) via case note audit based on LMP and U/S report
Timepoint [2] 301048 0
at birth
Secondary outcome [3] 301049 0
The safety and tolerability of DHA supplementation.
Tolerability: By structured interview, post-term induction/post-term pre-labour Csection:
medical case note audit based on LMP and U/S
Timepoint [3] 301049 0
Ongoing throughout the study.
Secondary outcome [4] 305048 0
Low Birth Weight (LBW): birth wt <2500g
Timepoint [4] 305048 0
at birth
Secondary outcome [5] 305049 0
Small for gestational age: birth wt < 10 centile for corresponding GA and sex.
Timepoint [5] 305049 0
at birth
Secondary outcome [6] 305067 0
Neonatal complications will be assessed via case note audit. The following complications will be recorded:
1. Jaundice required phototherapy
2. Hypoglycaemia required intravenous dextrose infusion
3. Neonatal convulsion
4. Brain injury
5. Surgery
6. Necrotising Enterocolitis (NEC)
7. Sepsis
8. Retinopathy of prematurity (ROP)
9. Other
Timepoint [6] 305067 0
up to 28 days post birth
Secondary outcome [7] 305068 0
Admission to neonatal intensive care unit via case note audit
Timepoint [7] 305068 0
up to 28 days post birth

Eligibility
Key inclusion criteria
A singleton or multiple pregnancy and less than 20 weeks gestation.

Able to give informed consent.
Minimum age
No limit
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Women with a known fetal abnormality will be excluded.

Women who are taking dietary supplements containing LCPUFA > 150mg/day.

Women who are taking dietary supplements containing LCPUFA < / = 150mg/day and are not willing to stop.

Women with bleeding disorders where fish oil is contraindicated or are on anticoagulant therapy.

Women with a history of drug or alcohol abuse.

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)
Women will be approached to enter the trial by research staff at the time of attending the hospital for their first antenatal booking visit. If they are interested in the study, they will be screened and have the study explained to them. When all the inclusion and exclusion criteria have been checked and the eligibility of the women confirmed, a copy of the information sheet and consent form will be given to the women.

The information sheet will describe the prurpose of the study, the procedures to be followed, and the risks and benefits of participation. The research staff will conduct the informed consent discussion and will check that information provided is understood and answer any questions about the study. Consent will be voluntary and free from coercion.

Upon receiving written informed consent, a research staff member will collect baseline data including contact details, birth order, age, weight, height, heighest level of education, occupation, smoking status and pregnancy related background data. A blood sample will also be collected to assess fatty acid status. Women will then be randomly assigned to treatment or control group. A copy of the information sheet and signed consent form will be provided to the women and the original filed in the case report form (CRF).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Women will be assigned to study packs labelled with a unique study number assigned through a web-based randomisation service. Allocation will follow a computer generated randomisation schedule with balanced variable blocks, prepared by an independent consultant. Stratification will be by centre and supplements used prior to trial entry (containing no LCPUFA vs. less than or equal to 150mg LCPUFA/day).

Each study pack will contain either treatment or control capsules, pre-packed according to the randomisation schedule. Participants and their family, care providers, outcome assessors and data analysts will be blinded to randomisation group.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
All analyses will be performed on an intention-to-treat basis. The primary outcome of early preterm birth will be compared between treatment and control groups using log binomial regression. Adjustment will be made for the stratification variables centre and supplements, as well as pre-specified prognostic baseline variables. Results will be presented as a relative risk with confidence interval and 2-sided p-value. Statistical significance will be assessed accounting for the pre-specified interim analysis using the O'Brien-Fleming approach. All analyses will follow a pre-specified statistical analysis plan. Infant outcomes will be analysed using generalised estimating equations to account for clustering due to multiple births.

Missing data (deaths) will be multiple imputed. Sensitivity analyses will also be performed using the original unimputed data, excluding deaths.

The sample size estimation was based on our published DOMInO trial (Makrdies et al, JAMA, 2010; 304: p 1675-83) of women with singleton pregnancies, treatment resulted in a 1.16% absolute reduction (from 2.25% to 1.09%) in the incidence of early preterm birth (EPTB). Inclusion of women with multiple pregnancies in the ORIP trial is expected to result in a small increase in the incidence of EPTB in both treatment groups, since EPTB is more common in multiple pregnancies. To demonstrate an absolute reduction in the incidence of EPTB of 1.16% (from 2.45% to 1.29%) with 85% power and overall two-sided alpha=0.05, a sample size of 2618 per group (i.e. 5236 total) is required. Allowing for a loss to follow up of 5%, a total of 5540 women is required to ensure adequate power for the primary outcome. Since EPTB is a mother level outcome, the sample size calculations define the number of mothers that need to be recruited and no adjustment for clustering due to multiple pregnancies is required for this outcome.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
21/10/2013
Actual
1/11/2013
Date of last participant enrolment
Anticipated
31/12/2017
Actual
28/04/2017
Date of last data collection
Anticipated
24/11/2017
Actual
29/12/2017
Sample size
Target
5540
Accrual to date
Final
5544
Recruitment in Australia
Recruitment state(s)
QLD,SA,WA,VIC
Recruitment hospital [1] 555 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [2] 556 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [3] 4856 0
Werribee Mercy Hospital - Werribee
Recruitment hospital [4] 4857 0
Mater Mother's Hospital - South Brisbane
Recruitment hospital [5] 4858 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [6] 11526 0
Joondalup Health Campus - Joondalup
Recruitment postcode(s) [1] 12361 0
3030 - Werribee
Recruitment postcode(s) [2] 12363 0
4101 - South Brisbane
Recruitment postcode(s) [3] 6294 0
5006 - North Adelaide
Recruitment postcode(s) [4] 6295 0
5042 - Bedford Park
Recruitment postcode(s) [5] 12362 0
5112 - Elizabeth Vale
Recruitment postcode(s) [6] 23551 0
6027 - Joondalup

Funding & Sponsors
Funding source category [1] 286705 0
Government body
Name [1] 286705 0
National Health and Medical Research Council
Country [1] 286705 0
Australia
Primary sponsor type
Other
Name
South Australian Health and Medical Research Institute
Address
North Adelaide, SA 5000
Country
Australia
Secondary sponsor category [1] 285476 0
None
Name [1] 285476 0
Address [1] 285476 0
Country [1] 285476 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288771 0
Women's and Children's Health Network Human Research Ethics Committee
Ethics committee address [1] 288771 0
Level 2 Samuel Way Building
72 King William Rd
North Adelaide SA 5006
Ethics committee country [1] 288771 0
Australia
Date submitted for ethics approval [1] 288771 0
29/01/2013
Approval date [1] 288771 0
01/05/2013
Ethics approval number [1] 288771 0
HREC/13/WCHN/10

Summary
Brief summary
Early preterm birth (EPTB) is the major cause of perinatal mortality, serious neonatal morbidity and moderate to severe childhood disability in developed countries. Currently, effective broadly applicable primary prevention strategies to reduce the risk of EPTB in the general population are lacking. This randomised controlled trial will determine whether n-3 LCPUFA supplementation from mid-pregnancy (before 20 weeks gestation) to 34 weeks gestation reduces the risk of EPTB. The study is a double blind, randomised controlled multi-centre trial. The primary outcome is the Incidence of early preterm birth (EPTB) defined as delivery before 34 completed weeks gestation. Secondary outcomes include Incidence of post-term induction or post-term pre-labour caesarean section, other outcomes known to be directly affected by EPTB, and the safety and tolerability of DHA supplementation. Eligible women will be randomly allocated to either intervention (~800 mg DHA) or control groups.. Women will receive intervention from trial entry (<20 weeks) to 34 weeks gestation or birth, whichever comes first. Women will be followed up to discharge after birth. The study will be conducted over a 5 year period 2013 to 2017. A total of 5540 pregnant women will be recruited to take part in the trial.
Trial website
Trial related presentations / publications
Zhou SJ, Best K, Gibson R, et al. Study protocol for a randomised controlled trial evaluating the effect of prenatal omega-3 LCPUFA supplementation to reduce the incidence of preterm birth: the ORIP trial. BMJ Open 2017;7:e018360. doi:10.1136/ bmjopen-2017-018360

Makrides M, Best K, Yelland L, McPhee A, Zhou S, Quinlivan J, Dodd J, Atkinson E, Safa H, van Dam J, Khot N, Dekker G, Skubisz M, Anderson A, Kean B, Bowman A, McCallum C, Cashman K, Gibson R. A Randomized Trial of Prenatal n-3 Fatty Acid Supplementation and Preterm Delivery. N Engl J Med. 2019 Sep 12;381(11):1035-1045. doi: 10.1056/NEJMoa1816832. PMID: 31509674.

Best KP, Gibson RA, Yelland LN, Leemaqz S, Gomersall J, Liu G, Makrides M. Effect of omega-3 lcpufa supplementation on maternal fatty acid and oxylipin concentrations during pregnancy. Prostaglandins Leukot Essent Fatty Acids. 2020 Nov;162:102181. doi: 10.1016/j.plefa.2020.102181. Epub 2020 Sep 28. PMID: 33038832.

Simmonds LA, Sullivan TR, Skubisz M, Middleton PF, Best KP, Yelland LN, Quinlivan J, Zhou SJ, Liu G, McPhee AJ, Gibson RA, Makrides M. Omega-3 fatty acid supplementation in pregnancy-baseline omega-3 status and early preterm birth: exploratory analysis of a randomised controlled trial. BJOG. 2020 Jul;127(8):975-981. doi: 10.1111/1471-0528.16168. Epub 2020 Mar 3. PMID: 32034969.
Public notes
Attachments [1] 2918 2918 0 0
/AnzctrAttachments/363566-Study protocol for a randomised controlled trial evaluating the effect of prenatal omega-3 LCPUFA supplementation to reduce the incidence of preterm birth_the ORIP trial.pdf (Protocol)

Contacts
Principal investigator
Name 37322 0
Dr Shao (Jo) Zhou
Address 37322 0
FOODplus Research Centre
The University of Adelaide, Waite Campus
PMB 1
Glen Osmond SA 5064
Country 37322 0
Australia
Phone 37322 0
+61 8 8313 2065
Fax 37322 0
+61 8 8303 7135
Email 37322 0
jo.zhou@adelaide.edu.au
Contact person for public queries
Name 37323 0
Dr Karen Best
Address 37323 0
SAHMRI, North Terrace, Adelaide SA 5000 Australia
Country 37323 0
Australia
Phone 37323 0
+61 8 8128 4404
Fax 37323 0
+61 8 8239 0267
Email 37323 0
karen.best@sahmri.com
Contact person for scientific queries
Name 37324 0
Prof Maria Makrides
Address 37324 0
SAHMRI, North Terrace, Adelaide SA 5000 Australia
Country 37324 0
Australia
Phone 37324 0
+618 8128 4416
Fax 37324 0
+61 8 8303 7135
Email 37324 0
maria.makrides@sahmri.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Yes. De-identified, individual participant data (IPD) that underlie the results reported in the primary paper (text, tables, figures and appendices) will be available. Dataset(s) will be limited to those participants and variables that are necessary for completion of the approved research proposal.
When will data be available (start and end dates)?
Data requests will be accepted beginning 3 months and ending 5 years after publication of trial results.
Available to whom?
Data will be available to researchers who provide a methodologically sound research proposal following review and approval by the trial steering committee and completion of a signed data
access agreement.
Available for what types of analyses?
Data may be shared with researchers who provide a methodologically sound research proposal following review and approval by the trial steering committee and completion of a signed data access agreement.
How or where can data be obtained?
All data requests should be made to maria.makrides@sahmri.com or karen.best@sahmri.com


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19556Study protocol   
19557Statistical analysis plan  maria.makrides@sahmri.com
19558Other  maria.makrides@sahmri.com Case Report Form



Results publications and other study-related documents

Documents added manually

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA randomized trial of prenatal n-3 fatty acid supplementation and preterm delivery.2019https://dx.doi.org/10.1056/NEJMoa1816832
EmbasePredictors of compliance with higher dose omega-3 fatty acid supplementation during pregnancy and implications for the risk of prematurity: exploratory analysis of the ORIP randomised trial.2023https://dx.doi.org/10.1136/bmjopen-2023-076507
N.B. These documents automatically identified may not have been verified by the study sponsor.