Condition category
Pregnancy and Childbirth
Date applied
05/09/2019
Date assigned
20/04/2020
Last edited
27/07/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
In the last months of pregnancy, babies who are smaller or who grow more slowly than expected are at higher risk of dying in the mother's womb. Some of these smaller babies who survive may have developmental problems later in infancy. Doctors have many ways to monitor such babies in the womb but, until the baby is born, the only treatment available is to deliver the baby.
If the pregnancy has reached its full term, induction of labour is the usual option. If the baby is preterm (before 37 weeks of pregnancy) the right course of action is less clear. Delivering the baby early, as soon as there are signs of problems, will minimise any damage due to lack of oxygen in the womb, but the baby may suffer harm as a result of being born prematurely. This study is looking at the balance of risks linked with continuing the pregnancy a little longer or delivering the baby early.

Who can participate?
Pregnant women whose babies are either smaller or growing more slowly than expected between 32 and 36 weeks of pregnancy, will be invited to participate in the study.

What does the study involve?
Babies will be closely monitored with ultrasound scans, Doppler tests for blood flow and computerised heart rate tests. All these tests are regularly used in normal maternity care and are safe. If the Doppler test shows changes in the blood flow to the baby’s brain, mothers will be randomly assigned to one of two groups: in one group the babies will be delivered immediately. In the other group the babies will continue to be monitored closely. Babies in the second group will be delivered if computerised analysis of the baby’s heart rate shows signs of deteriorating health. The health of all the babies will be recorded at birth, and their development checked at two years of age.

What are the possible benefits and risks of participating?
The timing of the baby’s birth will be chosen at random. The risks of being born too early are mainly of breathing problems for the baby and a very small risk of bleeding in the brain related to prematurity. The risks of waiting are that the baby’s condition may deteriorate rapidly such that he or she gets seriously short of oxygen. All of these risks are very small. Neither ultrasound nor baby heart rate monitoring will cause harm to the baby directly.

Patient and Public Involvement (PPI)
Sands, the stillbirth and neonatal death charity, is the main stillbirth support charity in the UK and has been closely involved in the development and design of TRUFFLE 2 RCT. Senior SANDS Research Members (Charlotte Bevan and Laura Price) took part in TRUFFLE meetings in Naples 2016 and Berlin 2017. Sands is clear that there is an urgent need for better assessment and care of women and their babies in late pregnancy and supports the study.
The topic of this trial has also been prioritised by the Royal college of Obstetrics and Gynaecology’s (RCOG) Stillbirth Clinical Studies Group, and addresses three of the James Lind Alliance (JLA) Stillbirth Priority Setting Partnership’s priorities. The study is closely aligned with the NHS ‘Saving Babies’ Lives Care Bundle’, one of whose four key components is detection of fetal growth restriction. The study also has support from patient groups aligned with the European TRUFFLE centres. As part of the Feasibility Study (www.truffle-study.org), 14 women commented on the objectives of the trial as a pilot in one centre. All supported the objectives and 12/14 would consider participation.

Where is the study run from?
Imperial College NHS Trust (UK)

When is the study starting and how long is it expected to run for?
June 2020 to May 2025

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

Who is the main contact?
Prof. Christoph Lees, christoph.lees@nhs.net

Trial website

http://www.truffle-study.org/

Contact information

Type

Scientific

Primary contact

Prof Christoph Lees

ORCID ID

http://orcid.org/0000-0002-2104-5561

Contact details

Queen Charlotte's and Chelsea Hospital
DuCane Road
London
W12 0HS
United Kingdom
+44 (0) 20 759 42104
christoph.lees@nhs.net

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

19QC5491, CPMS 45166, NIHR127976, IRAS 266400

Study information

Scientific title

Perinatal and 2 year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 Randomised Trial

Acronym

TRUFFLE 2

Study hypothesis

Current study hypothesis as of 27/07/2020:
Delivery on the basis of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity without a worsening of neurodevelopmental outcome at 2 years.

Previous study hypothesis:
Delivery on the basis of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity (efficacy outcome)

Ethics approval

Approved 04/02/2020, Ethics Board: London Riverside Research Ethics Committee (Chelsea & Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK; +44 (0)207 104 8340, 0207 104 8199; riverside.rec@hra.nhs.uk), REC ref: 20/LO/0031

Study design

Multicentre individually randomized controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Fetal growth restriction

Intervention

Current interventions as of 27/07/2020:
Women will be randomised to delivery or conservative management (cCTG monitoring and traditional ultrasound). The randomisation process will be completed through the CASTOR website.

Participants in the immediate delivery (intervention) arm will be delivered (or induction of labour started) within 48 hours, allowing for administration of corticosteroids and infusion of magnesium sulphate as per local protocol/guidance.

Participants in the delayed delivery (control) arm will be closely monitored using twice-weekly Doppler and cCTG monitoring. Delivery is indicated when STV < 4.5msec on cCTG or there are repeated decelerations.

Assessment of the primary outcome will be at infant discharge from the NNU and assessment of the key secondary infant outcomes using the general health questionnaire and PARCA-R. The general health questionnaire will be sent out by the Castor website at 6, 12, 18 and 24 months postpartum. Neurodevelopment will be assessed at 2 years age corrected for prematurity using parent-report: PARCA-R. The window for determining 2-year outcome will be from 22-28 months over which range the PARCA-R has been standardised.

Previous interventions:
Women will be randomised to delivery or conservative management (cCTG monitoring and traditional ultrasound). The randomisation process will be completed through the CASTOR website.

Participants in the delivery arm will be delivered within 48 hours, allowing for administration of corticosteroids and infusion of magnesium sulphate as per local protocol/guidance.

Participants in the conservative arm will be closely monitored using twice-weekly Doppler and cCTG monitoring. UCR may be measured in this time but women may not be delivered based on this. Delivery is indicated when STV < 4.5msec on cCTG or there are repeated decelerations.

Two-year developmental outcomes - research administrators will contact the women at 20 - 22 months corrected age in order to establish baby’s whereabouts and discuss the PARCA-R test which must be performed at 24 months and establish in which language this should be tested. After the PARCA-R is undertaken by the parents, the questionnaire is sent back to the central two year follow up assessment office of University College London (or, if this is not possible a jpeg or pdf may be emailed) for scoring and data entry to the CASTOR website.

Intervention type

Other

Phase

Drug names

Primary outcome measure

Current primary outcome measure as of 27/07/2020:
Composite poor condition at birth and neonatal adverse outcome. Any of the following:
1. Poor condition at birth
1.1. Apgar score at 5 minutes <7, arterial pH of <7.0 or venous pH of <7.1
1.2. Resuscitation with intubation, chest compressions or medication
2. Fetal death/death before neonatal hospital discharge
3. Neonatal brain injury syndromes
3.1. Infants with a diagnosis consistent with hypoxic ischaemic encephalopathy: term and near-term infants only
3.2. Infants with a diagnosis of intracranial haemorrhage, perinatal stroke, hypoxic ischaemic encephalopathy (HIE), central nervous system infection, and kernicterus (bilirubin encephalopathy): all infants
3.3.Preterm white matter disease (periventricular leukomalacia): preterm infants only
3.4. Infants with a recorded seizure confirmed by EEG
4. Respiratory support
4.1. Need for mechanical support of respiration after admission to NNU, for more than 1 hour – includes need for continuous positive airways pressure (CPAP or NIPPV) or mechanical ventilation via and endotracheal tube – but excludes need for supplemental oxygen
5. Cardiovascular abnormality
5.1. Hypotensive treatment, ductus arteriosus treatment, or disseminated coagulopathy
6. Sepsis (clinical sepsis with positive blood culture, or necrotising enterocolitis requiring surgery)
7. Retinopathy of prematurity requiring treatment (laser or anti-VEGF injections)

Previous primary outcome measure:
Success of delivery measured using:
1. Intrauterine fetal death or neonatal death before hospital discharge
2. Gestational age at delivery
3. Birthweight
4. Birth condition (Apgar score, cord pH)
5. Admission to neonatal unit
6. Neonatal brain injury syndromes
7. Respiratory support
8. Number of neonatal unit admission days
9. Level of neonatal care
10. Morbidity including duration of respiratory support, chronic lung disease, severe intraventricular haemorrhage grade III/IV, necrotising enterocolitis requiring surgery, retinopathy of prematurity requiring treatment.

Secondary outcome measures

Current secondary outcome measures as of 27/07/2020:
For the baby:
1. Health and developmental outcomes assessed using PARCA-R questionnaire at 2 years and the general health questionnaire up to 2 years corrected age. The PARCA-R will be completed at 24 months from correct age. It allows the following scales to be derived: Non-verbal cognitive scale and language development scale. Raw scores from the scales are standardised (by corrected age and gender) to a notional population mean of 100 SD=15 and the average of these two component scores will be taken as the overall composite score. Corrected age is where preterm babies (born before 37 weeks) use estimate date of delivery as opposed of date of birth.
2. The general health questionnaire (REF) will be used to derive the following health outcomes at 6, 12, 18 and 24 months postpartum:
2.1. Use of ANY hospital service (yes/no) and total number of contacts over the 2 year period
2.2. Admitted to hospital (yes/no) and total number of admissions over the 2 year period
2.3. Planned/unplanned admissions to hospital (yes/no) over the 2 year period
2.4. Intensive care or not over the 2 year period
2.5. Attended A&E (and not subsequently admitted) (yes/no) over the 2 year period
2.6. Attended Outpatients/clinic (yes/no) over the 2 year period

For the mother:
1. Gestational hypertension as defined by the International Society for Trial of Hypertension in pregnancy (ISSHP): hypertension (blood pressure ≥140/90mmHg) arising de novo after 20 weeks gestation in the absence of proteinuria
2. Pre-eclampsia as defined by the ISSHP: (blood pressure ≥140/90mmHg AND significant proteinuria (protein/creatinine ratio of 30 mg/mmol)
3. Onset of labour (spontaneous, induction (method), prelabour cesarean)
4. Mode of delivery (spontaneous vaginal, assisted vaginal, caesarean)

Previous secondary outcome measures:
1. For the baby:
Two-year developmental outcomes assessed by the PARCA-R performed at 24 months
2. For the mother:
2.1 Pre-eclampsia, as defined by the International Society for Study of Hypertension in pregnancy (ISSHP): (blood pressure ≥140/90mmHg AND significant proteinuria (protein/creatinine ratio of 30 mg/mmol)
2.2 Induction of labour (method)
2.3 Mode of delivery (spontaneous vaginal, assisted vaginal, caesarean)

Overall trial start date

01/12/2019

Overall trial end date

31/05/2025

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 27/07/2020:
All criteria should be fulfilled to be eligible for randomisation:
1. Women ≥ 18 years old
2. Pregnant with singleton non-anomalous fetuses
3. Between 32+0 and 36+6 weeks of gestation
4. Estimated fetal weight or abdominal circumference <10th percentile OR decreased by 50 percentiles since an ultrasound scan at 18+0-32+0 weeks
5. Cerebral redistribution defined as UCR >1.0 (32+0-33+6 weeks) or >0.8 (34+0-36+6 weeks) measured at least twice in any 24 hours period
6. Normal STV on cCTG (4.5 msec or above)

Previous inclusion criteria:
For screening:
1. Women ≥ 18 years old
2. Pregnant with singleton fetuses at risk of compromise:
2.1 Between 32+0 and 36+6 weeks of gestation and
2.2 Estimated fetal weight or abdominal circumference <10th percentile OR abdominal circumference decreased by 50 percentiles from 18-22 week scan

For randomisation:
3.1 Cerebral redistribution defined as UCR z-score >1.5 (32-33+6 weeks) / >1.0 (34-36+6 weeks) and:
3.2 Normal STV on cCTG (> 4.5msec) and:
3.3 No contraindications to either trial treatment arm

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

780 participants per arm are required, giving 1,560 in total

Participant exclusion criteria

Current exclusion criteria as of 27/07/2020:
1. Indication for immediate delivery required within 48 hours
2. Unable to give informed consent
3. Preterm prelabour rupture of the membranes (PPROM)
4. Suspected placental abruption or antepartum haemorrhage
5. Presence of reversed end diastolic flow in the Umbilical Artery

Previous exclusion criteria:
1. Indication for immediate delivery within 48 hours
2. Unable to give informed consent
3. Preterm prelabour rupture of the membranes (PPROM)
4. Suspected placental abruption or antepartum haemorrhage

Recruitment start date

01/10/2020

Recruitment end date

30/11/2022

Locations

Countries of recruitment

Austria, Belgium, Czech Republic, Estonia, Germany, Italy, Norway, United Kingdom

Trial participating centre

Queen Charlotte's and Chelsea Hospital
Imperial College NHS Trust DuCane Road
London
W12 0HS
United Kingdom

Trial participating centre

Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2WB
United Kingdom

Trial participating centre

Liverpool Women's NHS Foundation Trust
Crown Street
Liverpool
L8 7SS
United Kingdom

Trial participating centre

The Princess Alexandra Hospital NHS Trust
Hamstel Road
Harlow
CM20 1QX
United Kingdom

Trial participating centre

Queens Medical Centre
Nottingham University Hospitals NHS Trust Derby Road
Nottingham
NG7 2UH
United Kingdom

Trial participating centre

St George's Hospital
St George's University Hospitals NHS Foundation Trust Blackshaw Road Tooting
London
SW17 0QT
United Kingdom

Trial participating centre

St. James's University Hospital
Leeds Teaching Hospitals NHS Trust Beckett Street
Leeds
LS9 7TF
United Kingdom

Trial participating centre

East Suffolk and North Essex NHS Foundation Trust
Colchester District General Turner Road
Colchester
CO4 5JL
United Kingdom

Trial participating centre

University College London Hospitals NHS Foundation Trust
250 Euston Road
London
NW1 2PG
United Kingdom

Trial participating centre

Chelsea and Westminster Hospital NHS Foundation Trust
369 Fulham Road
London
SW10 9NH
United Kingdom

Trial participating centre

Guy’s & St Thomas’ NHS Foundation Trust
Great Maze Pond
London
SE1 7EH
United Kingdom

Sponsor information

Organisation

Imperial College London

Sponsor details

Joint Research Compliance Office
Room 215
Level 2
Medical School Building
Norfolk Place
London
W2 1PG
United Kingdom
02075949459
becky.ward@imperial.ac.uk

Sponsor type

University/education

Website

Funders

Funder type

Not defined

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer-reviewed journal

IPD sharing statement:
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request

Intention to publish date

31/12/2025

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

27/07/2020: The following changes were made to the trial record: 1. The study hypothesis, ethics approval, interventions, primary and secondary outcome measures, inclusion and exclusion criteria were updated. 2. The overall trial end date was changed from 31/12/2024 to 31/05/2025. 3. The recruitment start date was changed from 01/06/2020 to 01/10/2020. 4. The recruitment end date was changed from 01/12/2022 to 30/11/2022. 22/04/2020: Internal review. 04/10/2019: Trial’s existence confirmed by National Institute for Health Research (NIHR)