The PIONEER Study - A study to investigate whether taking the medication Pravastatin reduces the number of babies born too early (preterm, i.e., before 37 weeks of pregnancy) and, if so, how it works in the body to do this.

Plain English Summary

Background and study aims
Around 7 out of every 100 UK babies are born too early (preterm, i.e., before 37 weeks of pregnancy). Being born preterm is the most common cause of babies dying before the age of one year in the UK; 1 in 3 of those who survive are diagnosed with cerebral palsy. This study will test whether the medicine Pravastatin reduces the number of babies born preterm. It is not fully understood why some babies are born early, and there are few effective treatments to prevent this from happening. Research shows it is likely that early labour may occur because of types of inflammation in the mother’s body. Taking a medication which reduces inflammation, such as Pravastatin, could therefore reduce the number of babies being born preterm. Pravastatin has been tested for the treatment and prevention of other pregnancy problems, with no safety concerns for women or their babies, and some studies suggest that it may reduce the number of babies born preterm. This study will test whether taking one tablet of Pravastatin once a day, from between 16-20 weeks of pregnancy until 37 weeks, reduces the number of babies born too early.

Who can participate?
Young and adult women aged 16 years old and over who attend Preterm Birth Prevention clinics

What does the study involve?
Participants will be asked if they would like to join the study. If they join, half will be given Pravastatin and half will be given a placebo (a dummy tablet which looks like Pravastatin but does not contain Pravastatin). Neither the women nor the researchers will know which tablets they are taking until the end of the study. The study will record how many weeks of pregnancy their babies are born and compare this between the two groups of women. The study will also measure levels of certain bacteria and markers of inflammation, which may be related to babies being born early, by collecting blood, fluid produced in the vagina and stool samples. Any complications the women or their babies have will be recorded and the babies’ development will be assessed at two years of age.

What are the possible benefits and risks of participating?
There is a possibility that participants who receive Pravastatin will have a lower chance of preterm birth, but we cannot be certain. This is what this study will help us to find out. If Pravastatin does have this effect, the research could help us to improve the options for pregnant women who are at risk of preterm birth in the future. Participants may also benefit from the increased contact that comes with being a part of a clinical study.

The potential risks and burdens for the trial are summarised in the Participant Information Sheet (PIS), which has been reviewed and approved by our public contributors.
• Possible side effects from the trial medication. These are explained in the PIS, including how likely they are to occur, with clarity that side effects relate to the participant and not their baby.
• Discomfort or pain when having a blood sample taken. Localised bruising and discomfort can occur at the site of venipuncture. Infrequently fainting may occur. Blood samples must be taken from all participants to confirm eligibility and at 28 weeks to assess liver transaminase levels (ALT or AST) - additional blood samples will be taken from all participants at sites taking part in the mechanistic sub-study. Samples will be taken by trained phlebotomists and every effort will be made to reduce pain or discomfort.
• Mild discomfort when having a vaginal swab taken (only participants in the mechanistic sub-study). This will be done by trained clinical staff who are experienced in taking these swabs and will be conducted in such a manner as to maintain privacy and dignity.
• Loss of participant's time to attend research visits at the hospital, take part in qualitative interviews or complete follow-up at home. Trial activities will be integrated into usual care visits where possible to reduce the burden of participation, and researchers will make efforts to arrange visits/calls for convenient times. Participants will also be reimbursed for some expenses.

Where is the study run from?
University Hospitals Bristol and Weston NHS Foundation Trust

When is the study starting and how long is it expected to run for?
February 2024 to February 2028

Who is funding the study?
National Institute for Health and Care Research (NIHR)

Who is the main contact?
pioneer-trial@bristol.ac.uk

Study website

https://bristol-trials-centre.bristol.ac.uk/details-of-studies/pioneer/

Type

Scientific, Principal Investigator

Contact name

Dr Katherine Birchenall

ORCID ID

http://orcid.org/0000-0002-7261-4832

Contact details

Women and Children's Health
University Hospitals Bristol and Weston NHS Foundation Trust
Bristol
BS8 1NU
United Kingdom
None provided
katherine.birchenall@bristol.ac.uk

Type

Public

Contact name

Dr Taemi Kawahara

ORCID ID

Contact details

PIONEER Central Trial Office
Bristol Trials Centre
Bristol Medical School
University of Bristol
1-5 Whiteladies Road
Bristol
BS8 1NU
United Kingdom
+44 (0)117 4560633
pioneer-trial@bristol.ac.uk

EudraCT/CTIS number

Nil known

IRAS number

1007563

ClinicalTrials.gov number

Nil known

Protocol/serial number

OG/2022/7409, IRAS 1007563, CPMS 60531

Scientific title

PravastatIn tO preveNt prEtErm biRth (PIONEER): a parallel group randomised placebo-controlled trial

Acronym

PIONEER

Study hypothesis

We are interested to find out whether treatment with a statin, Pravastatin, reduces the chance a person will have a preterm birth by extending the length of pregnancy and so reducing the risks associated with babies being born too soon.

We would also like to find out how Pravastatin might work to reduce preterm birth by looking at blood samples, vaginal swabs and stool samples taken from some of the pregnant people who take part in the trial.
We will also see whether Pravastatin has an effect on a number of outcomes which have been selected as being important to this population. Some of these relate to the mother, for example whether they had an infection after birth, and some relate to the child, for example did they need to go to intensive care after birth.
Finally, we will ask some of the people who take part in the trial to complete a questionnaire when their child is 2 years old, to look at the childs' development.

Ethics approval(s)

Approved 16/04/2024, North West - Greater Manchester Central Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; None provided; gmcentral.rec@hra.nhs.uk), ref: 24/NW/0074

Study design

Interventional double blind randomized parallel group placebo controlled trial

Primary study design

Interventional

Secondary study design

Randomised parallel trial

Study setting(s)

Hospital

Study type

Safety, Efficacy

Patient information sheet

Condition

Intermediate or high risk for preterm birth

Intervention

Participants will be randomised in a 1:1 ratio to receive either Pravastatin or placebo. Randomisation will be performed via the trial database using Sealed Envelope.
Participants randomised to the intervention group will receive Pravastatin 20mg and participants randomised to the placebo group will receive a matched tablet with no active substance. Both will be taken orally once daily by participants, from between 16+0 and 20+0 weeks gestation until 37+0 weeks gestation. Treatment may be stopped earlier (reasons are detailed in the protocol).
All participants will be followed up until birth or loss of pregnancy. Participants recruited in the first 18 months of the trial will be asked to complete a questionnaire when their child is two years old.

Intervention type

Drug

Pharmaceutical study type(s)

Pharmacodynamic, Prophylaxis, Therapy, Others (Qualitative evaluation - aims to explore any challenges or obstacles for recruitment and to optimise unbiased trial information delivery to ensure full informed consent is standardised at all sites.)

Phase

Phase III

Drug/device/biological/vaccine name(s)

Pravastatin

Primary outcome measure

Gestational age, in days, at birth, measured using patient records.

Secondary outcome measures

1. Maternal and neonatal secondary outcomes:
Maternal secondary outcomes: maternal mortality; antenatal infection requiring antibiotics; intrapartum infection requiring antibiotics; development of pre-eclampsia; PPROM; harm to mother from intervention; cervical cerclage; progesterone use; shortest cervical length measured.
Neonatal secondary outcomes: Premature birth (categorising <37 weeks' gestation, and <34 weeks gestation); Apgar scores at 1, 5, and 10 minutes of age; admission to Neonatal Intensive Care Unit (NICU); birthweight; early neurodevelopmental morbidity; gastrointestinal and respiratory morbidity; neonatal mortality; infection requiring antibiotics; need for respiratory support; harm to offspring from intervention. Collected from hospital databases following birth and discharge from hospital admission.
2. Mechanism of action of Pravastatin, evaluated using mechanistic studies to assess maternal:
2.1. Cervicovaginal fluid concentrations of inflammatory markers of interest, including IL-8, IL-6, IL-2, MBL, IgG1, IgG3, C3b and C5a;
2.2. Vaginal microbiota profile;
2.3. Serum lipid profile: very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) assessed via NMR metabolomics; and,
2.4. Stool microbiota profile and metabolomics profile.
2.5. Maternal blood inflammatory profile.
Samples collected as baseline, 24 weeks' gestation and 28 weeks' gestation.
3. For the offspring of pregnancies for those participants recruited during the first 18 months of the trial only. Assessment of child's cognitive and language development using the Parent Report of Children’s Abilities-Revised (PARCA-R) questionnaire. Questionnaire completed at 2 years corrected age for child.

Overall study start date

15/02/2024

Overall study end date

29/02/2028

Reason abandoned (if study stopped)

Participant inclusion criteria

1. Pregnant people with a singleton pregnancy identified as being at high or intermediate risk for PTB according to criteria detailed in the Saving Babies’ Lives Care Bundle (V3), where:
1.1. High risk - at least one of the following:
1.1.1. Previous mid-trimester loss >16 weeks' gestation;
1.1.2. Previous PTB <34 week's gestation;
1.1.3. Previous Preterm Premature Rupture of Membranes (PPROM) <34 weeks’ gestation;
1.1.4. Previous use of cervical cerclage;
1.1.5. Known uterine structural variant;
1.1.6. Intrauterine adhesions;
1.1.7. History of trachelectomy (for cervical cancer).
OR
1.2. Intermediate risk - at least one of the following:
1.2.1. Previous birth by caesarean section at full dilatation;
1.2.2. History of significant excision of cervical cells (e.g., Large Loop Excision of Transformation Zone (LLETZ) where >15mm depth removed, or >1 LLETZ procedure carried out or cone biopsy).
2. Between 16+0- and 20+0 weeks’ gestation at randomisation.

Participant type(s)

Patient

Age group

Mixed

Lower age limit

16 Years

Sex

Female

Target number of participants

750

Participant exclusion criteria

1. Multiple pregnancy
2. <16 years of age
3. Hypersensitivity to Pravastatin (active substance or any of the excipients)
4. Personal or first-degree relative with heritable muscle disorder
5. Participating in the active phase of another CTIMP
6. Lactose intolerance
7. >14 units alcohol/week
8. Past/current liver disease
9. ALT or AST above upper limit of normal (as set by local laboratories), to be taken at the time of screening*
10. Bilirubin above upper limit of normal (as set by local laboratories), to be taken at the time of screening*
11. Creatine Kinase (CK) concentration >5 times upper limit of normal (as set by local laboratories), to be taken at the time of screening
12. Currently breastfeeding
13. Unable to provide informed consent
14. Previously participated in PIONEER
15. Currently taking medicines or groups of medicines that are contraindicated for concomitant use with pravastatin§

* It is acknowledged that the Liver Function Test may include different assessments at different sites, therefore for the purpose of the screening blood test, the term “Liver Function Test” at screening should include measurement of Bilirubin and at least one of ALT or AST. If any of these are above the upper limit of the normal, the person would not be eligible for inclusion in PIONEER, and should have ongoing follow-up according to local policy.
§ Those taking macrolides should be excluded from PIONEER, however, if a limited course of macrolides are prescribed with the course due to complete prior to 20+0 weeks’ gestation, then it may be possible to recruit to PIONEER following completion of the course of antibiotics (if completion of the course of antibiotics is prior to 20+0).

Recruitment start date

01/07/2024

Recruitment end date

31/03/2027

Countries of recruitment

United Kingdom

Study participating centre

Birmingham Womens Hospital
Womens Health Care
Mindelsohn Way
Birmingham
B15 2TG
United Kingdom

Study participating centre

St Michaels Hospital
Southwell Street
Bristol
BS2 8EG
United Kingdom

Study participating centre

Southmead Hospital
Southmead Road
Westbury-on-trym
Bristol
BS10 5NB
United Kingdom

Study participating centre

St James's University Hospital
Gledow Wing
Beckett Street
Leeds
LS9 7TF
United Kingdom

Study participating centre

University Hospital (coventry)
Clifford Bridge Road
Coventry
CV2 2DX
United Kingdom

Study participating centre

St Thomas' Hospital
Westminster Bridge Road
London
SE1 7EH
United Kingdom

Study participating centre

Jessops Wing
Royal Hallamshire Hospital
Glossop Road
Sheffield
S10 2JF
United Kingdom

Study participating centre

Hammersmith Hospital
Du Cane Road
Hammersmith
London
W12 0HS
United Kingdom

Study participating centre

The Royal Infirmary of Edinburgh
51 Little France Crescent
Edinburgh
EH16 4SA
United Kingdom

Study participating centre

West Cumberland Hospital
Homewood
Hensingham
Whitehaven
CA28 8JG
United Kingdom

Study participating centre

Norfolk and Norwich University Hospital
Colney Lane
Colney
Norwich
NR4 7UY
United Kingdom

Study participating centre

Birmingham Heartlands Hospital
Bordesley Green East
Bordesley Green
Birmingham
B9 5SS
United Kingdom

Study participating centre

Princess Anne Hospital
Coxford Road
Southampton
SO16 5YA
United Kingdom

Study participating centre

Royal Devon and Exeter Hospital
Royal Devon & Exeter Hospital
Barrack Road
Exeter
EX2 5DW
United Kingdom

Study participating centre

St. Richards Hospital
Spitalfield Lane
Chichester
PO19 6SE
United Kingdom

Study participating centre

Cumberland Infirmary
Newtown Road
Carlisle
CA2 7HY
United Kingdom

Study participating centre

The James Cook University Hospital
Marton Road
Middlesbrough
TS4 3BW
United Kingdom

Study participating centre

Burnley General Hospital
Casterton Avenue
Burnley
BB10 2PQ
United Kingdom

Study participating centre

St Marys Hospital
Oxford Road Site
Manchester
M13 9WL
United Kingdom

Study participating centre

Wythenshawe Hospital
Southmoor Road
Wythenshawe
Manchester
M23 9LT
United Kingdom

Study participating centre

Royal Oldham Hospital
Rochdale Road
Oldham
OL1 2JH
United Kingdom

Study participating centre

John Radcliffe Hospital
Headley Way
Headington
Oxford
OX3 9DU
United Kingdom

Study participating centre

Bradford Royal Infirmary
Duckworth Lane
Bradford
BD9 6RJ
United Kingdom

Study participating centre

University College London Hospital
235 Euston Road
London
NW1 2BU
United Kingdom

Study participating centre

University Hospital of Wales
Heath Park
Cardiff
CF14 4XW
United Kingdom

Organisation

University Hospitals Bristol and Weston NHS Foundation Trust

Sponsor details

Education and Research Centre
Level 3
Upper Maudlin Street
Bristol
BS2 8AE
England
United Kingdom
+44 (0)117 342 0233
R&DSponsorship@uhbw.nhs.uk

Sponsor type

University/education

Website

https://www.uhbristol.nhs.uk/research-innovation/

Funder type

Government

Funder name

National Institute for Health and Care Research

Alternative name(s)

National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Publication and dissemination plan

1. Peer reviewed scientific journals
2. Internal report
3. Conference presentation
4. Publication on website
5. Submission to regulatory authorities
6. Other
Data will not be made available for sharing until after publication of the main results of the trial. It is the trial team's intention to share underpinning research data in order to maximise reuse and evidence findings. The data will be deposited at the University of Bristol Research Data Repository (data.bris.ac.uk/data) where, once published, they will be assigned a doi: . A metadata record will be published openly by the repository and this record will clearly state how data can be accessed by bona fide researchers.
Anonymised recruitment consultation and interview transcripts may also be used to support teaching of qualitative research methods. We will store audio recordings, transcripts, and written feedback for 25 years, on secure University of Bristol servers. We will make transcripts “Controlled Access”. The anonymised transcripts will be stored in an online database and only made available to other researchers who secure the necessary approvals. All data will be anonymised before they are made available.
Access to the final trial dataset
Anonymous research data will be stored securely and kept for future analysis. Members of the TMG will develop a data sharing policy consistent with University of Bristol policy. Requests for access will be directed to the Research Data team at Bristol, who will assess the motives of potential data re-users before granting access to the data.

Intention to publish date

31/07/2029

Individual participant data (IPD) sharing plan

The datasets generated during the current trial will be available upon request after publication of the main results of the trial. The trial team intends to share underpinning research data to maximise reuse and evidence findings. The datasets will be deposited at the University of Bristol Research Data Repository (https://data.bris.ac.uk/data/) where, once published, they will be assigned a doi. A metadata record will be published openly by the repository and this record will clearly state how data can be accessed by bona fide researchers. The consent form for the trial includes the optional statement: “I agree to my information being stored securely and used for future research and training purposes. I understand that information shared will not include personally identifiable data.” As such, data will only be deposited from participants who agree to this statement.

IPD sharing plan summary

Stored in publicly available repository, Available on request

Study outputs