NeoCLEAR: optimising lumbar punctures in newborns

ISRCTN	ISRCTN14040914
DOI	https://doi.org/10.1186/ISRCTN14040914
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Integrated Research Application System (IRAS)	223737
Protocol serial number	35643
Sponsor	University of Oxford
Funder	NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 15/188/106

Submission date: 30/05/2018
Registration date: 26/06/2018
Last edited: 28/12/2023

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Nervous System Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Every year at least 15,000 newborns undergo a lumbar puncture to confirm suspected meningitis. Lumbar puncture technique varies in practice, and success rates are low (50-60%) meaning procedures need to be repeated, causing distress to the infants and their parents and extending treatment and hospital stay time. There is a pressing need for a large study to determine which lumbar puncture technique is the best approach. The aim of this study is to compare lumbar puncture techniques with the infant in a sitting position versus a lying position, and early versus late stylet removal.

Who can participate?
Newborns and infants in neonatal units and maternity wards who are having a lumbar puncture

What does the study involve?
The participants are randomly allocated to one of the following technique combinations:
1. Lying position and early stylet removal
2. Sitting position and early stylet removal
3. Lying position and late stylet removal
4. Sitting position and late stylet removal
The proportion of successful lumbar punctures is measured in the four groups.

What are the possible benefits and risks of participating?
The results of this trial will inform best practice, and ultimately, improved technique would result in fewer uninterpretable samples, fewer repeated procedures, reduced distress for infants and families, decreased antibiotic use and risk of antibiotic resistance, and reduced NHS costs due to fewer procedures, reduced length of stay, shorter antibiotic courses, and minimised antibiotic-associated complications. All of the methods used in the study are used routinely within UK hospitals. At the moment it is not known whether one method is better than others, so babies taking part could be given any of them.

Where is the study run from?
The University of Oxford (UK)

When is the study starting and how long is it expected to run for?
September 2017 to February 2021

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

Who is the main contact?
Christina Cole
neoclear@npeu.ox.ac.uk

Contact information

Ms Christina Cole
Scientific

National Perinatal Epidemiology Unit (NPEU)
Nuffield Department of Population Health
University of Oxford
Old Road Campus
Headington
Oxford
OX3 7LF
United Kingdom

Phone	+44 (0)1865 617923
Email	neoclear@npeu.ox.ac.uk

Study information

Primary study design	Interventional
Study design	Randomised; Interventional; Design type: Diagnosis, Other
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	NeoCLEAR: Neonatal Champagne Lumbar punctures Every time – An RCT. A multicentre, randomised controlled 2x2 factorial trial to investigate techniques to increase lumbar puncture success
Study acronym	NeoCLEAR
Study objectives	Every year at least 15,000 newborns undergo a lumbar puncture to confirm suspected meningitis. Lumbar puncture technique varies in practice, and success rates are low (50-60%) meaning procedures need to be repeated, causing distress to the infants and their parents and extending treatment and hospital stay time. There is a pressing need for a large randomised controlled trial to determine which lumbar puncture technique is the best approach. The trialists have designed a pragmatic (i.e a low level of trial-driven standards is enforced and sites work to their standard practices and processes for generalisability of the trial results), multi-centre, randomised controlled trial comparing two traditional lumbar puncture techniques: 1. The infant in sitting position versus lying position 2. Early versus late stylet removal The aim is to determine the optimal technique for performing lumbar puncture in infants. The results of this trial will inform best practice, and ultimately, improved technique would result in: 1. Fewer uninterpretable samples 2. Fewer repeated procedures 3. Reduced distress for infants & families 4. Decreased antibiotic use and risk of antibiotic resistance 5. Reduced NHS costs due to fewer procedures, reduced length of stay, shorter antibiotic courses, and minimised antibiotic-associated complications
Ethics approval(s)	South Central Hampshire-B, 12/06/2018, ref: 18/SC/0222
Health condition(s) or problem(s) studied	Meningitis
Intervention	Stratified block randomisation will be used to ensure balance between the groups with respect to the collaborating hospital and corrected gestational age at trial entry. The interventions compare: 1. Sitting position, in which the infant is held in a sitting position compared to lying (‘lateral decubitus’) position 2. Early stylet removal, which is the removal of the stylet from the hollow lumbar puncture needle shaft once it has penetrated the subcutaneous tissue before advancing the needle into the cerebrospinal fluid, compared to late stylet removal, which is removal of the stylet once it has been inserted into the expected cerebrospinal fluid space The participants will be randomly allocated (with equal chance i.e. 1:1:1:1) to one of the following technique combinations: 1. Lying position and early stylet removal 2. Sitting position and early stylet removal 3. Lying position and late stylet removal 4. Sitting position and late stylet removal Infants will be followed up until they are discharged home.
Intervention type	Procedure/Surgery
Primary outcome measure(s)	Proportion of infants with successful lumbar punctures, measured by whether cerebrospinal fluid is obtained and red blood cell count <10,000/mm3 on the first lumbar puncture procedure
Key secondary outcome measure(s)	Current secondary outcome measures as of 24/04/2020: The following short-term clinical, resource and safety outcomes have been defined as: 1. The proportion of infants with: 1.1. No cerebrospinal fluid (CSF) obtained, or pure blood/clotted, or blood-stained, or clear 1.2. CSF obtained and red blood cell (RBC) count <500, <5000, <10,000, or <25,000/mm3, or any RBC count 1.3. A CSF white blood cell (WBC) count not requiring a correction (whatever the RBC count) 2. Total number of procedures and attempts performed per infant 3. Proportion of infants diagnosed (by WBC count criteria, culture, Gram stain, and/or clinically) via CSF with: 3.1. Meningitis: WBC count 20 or more in CSF, or a true positive culture/polymerase chain reaction (PCR) (if RBC count is ≥500, the WBC count will be reduced by 1 for every 500 RBC counts to give a 'corrected' WBC count) 3.2. Equivocal: WBC count (or corrected WBC) <20, AND negative (or contaminated/incidental) culture and PCR with: 3.2.1. Polymorphonuclear leukocytes (PMN) >2 (and RBC count <500) OR 3.2.2. Organism found on Gram stain 3.3. Negative: WBC (or corrected WBC) count <20, PMN ≤2 (if RBC count <500), and negative (or contaminated/incidental) cultures, PCR, and Gram stain 3.4. Uninterpretable: No CSF obtained, or clotted, or CSF so bloody or insufficient that a cell count was impossible 4. CSF WBC, RBC, corrected WBC counts, PMNs and lymphocytes from the clearest sample 5. Time taken on first procedure from start of cleaning skin to removing needle at end of all attempts 6. Infant movement on first procedure using basic 4-point scale Outcomes relating to cost and safety: 7. In all infants, according to CSF-defined and clinically-defined diagnostic criteria: 7.1. Duration of the antibiotic course 7.2. Length of stay in surviving infants 7.3. Immediate complications related to LP: 7.3.1. Cardiovascular instability including oxygen saturations and heart rate 7.3.2. Respiratory deterioration (escalating respiratory support) post-LP 8. For the pilot phase: parental anxiety assessed using the State Trait Anxiety Inventory - State Subscale (STAI-S) Questionnaire Previous secondary outcome measures: Short-term clinical outcomes are measured by assessing: 1. The proportion of infants with: 1.1. No cerebrospinal fluid (CSF) obtained, or Pure blood/Clotted, or blood-stained, or clear 1.2. CSF obtained and red blood cell (RBC) count <500, <5,000, <10000, or <25000 /mm3, or any RBC count 1.3. A CSF white cell count not requiring a correction (whatever the RBC count) 2. Total number of procedures, and attempts within procedures, performed per infant to obtain interpretable CSF (RBC counts at the above thresholds) 3. Proportion of infants diagnosed (by WBC count criteria, culture, gram stain, and/or clinically) via CSF with: 3.1. Meningitis: WBC count 20 or more in CSF, or more than 2 PMNs, or a positive culture or gram stain, or clinically diagnosed (if RBC count is >500, the WBC count will be reduced by 1 for every 500 RBC counts to give a ‘corrected’ WBC count) 3.2. Equivocal: borderline white blood cell (WBC) counts, or uncertain culture result or uncertain clinical diagnosis 3.3. Negative: <20 CSF WBC count and 0–2 PMNs and negative cultures and gram stain and no clinical diagnosis of meningitis 3.4. Uninterpretable: no CSF obtained, or CSF so bloody that a cell count was impossible 4. CSF WBC, RBC, corrected WBC counts, PMNs, and lymphocytes, for any of the above 5. Time taken from start of cleaning skin to removing needle at end of all attempts 6. Infant movement assessed using a basic 4-point scale at time of procedure 7. Parental anxiety, measured using short-version STAI at baseline and within 48 hours of the first lumbar puncture procedure 8. Cost measured by assessing the duration of the antibiotic course from trial entry to discharge home 9. Cost measured by assessing the length of stay in hospital from trial entry until discharge home 10. Safety measured by assessing cardiovascular instability, including oxygen saturations and heart rate during the lumbar puncture procedure 11. Safety measured by assessing respiratory deterioration based on the requirement for escalating respiratory support within 1 hour of the lumbar puncture procedure
Completion date	28/02/2021

Eligibility

Participant type(s)	Patient
Age group	Neonate
Sex	All
Target sample size at registration	1020
Total final enrolment	1082
Key inclusion criteria	1. Neonates and infants in neonatal units and their maternity wards who are having a lumbar puncture 2. Parent(s) willing and able to give informed consent 3. Infants of corrected gestational age from 27+0 weeks to 44+0 weeks, AND working weight of 1,000 g or more 4. First lumbar puncture for current indication
Key exclusion criteria	Current exclusion criteria as of 24/04/2020: 1. Unable to be held in sitting position (including infants intubated and mechanically-ventilated) or other clinical condition which is likely, in the opinion of the treating clinician, to make sitting difficult, or which is likely to be compromised by sitting (e.g.open gastroschisis) 2. Previously randomised to the trial Previous exclusion criteria: 1. Unable to be held in sitting position (e.g. intubated and mechanically-ventilated) or other clinical condition which is likely to make sitting difficult, or which is likely to be compromised by sitting (e.g. open gastroschisis) 2. Previously randomised to the trial
Date of first enrolment	01/06/2018
Date of final enrolment	31/08/2020

Locations

Countries of recruitment

United Kingdom
England

Study participating centres

John Radcliffe Hospital (lead site)

Headley Way
Headington
Oxford
OX3 9DU
United Kingdom

Birmingham Heartlands Hospital

Bordesley Green East
Birmingham
B9 5SS
United Kingdom

Leicester Royal Infirmary

Infirmary Square
Leicester
LE1 5WW
United Kingdom

Northampton General Hospital

Cliftonville
Northampton
NN1 5BD
United Kingdom

Princess Anne Hospital

Coxford Road
Southampton
SO16 5YA
United Kingdom

Royal Berkshire Hospital

London Road
Reading
RG1 5AN
United Kingdom

Royal Hampshire County Hospital

Department of Paediatrics
Winchester
SO22 5DG
United Kingdom

Southmead Hospital

Southmead road
Westbury-on-Trym
Bristol
BS10 5NB
United Kingdom

St Michael's Hospital

Southwell Street
Bristol
BS2 8EG
United Kingdom

Bradford Royal Infirmary

Smith Lane
Bradford
BD9 6DA
United Kingdom

Colchester General Hospital

Turner Rd
Mile End
Colchester
CO4 5JL
United Kingdom

Derriford Hospital

Derriford Rd
Plymouth
PL6 8DH
United Kingdom

Gloucestershire Royal Hospital

Great Western Rd
Gloucester
GL1 3NN
United Kingdom

Great Western Hospital

Marlborough Rd
Swindon
SN3 6BB
United Kingdom

Medway Maritime Hospital

Windmill Road
Gillingham
ME7 5NY
United Kingdom

Norfolk and Norwich University Hospital

Colney Lane
Norwich
NR4 7UY
United Kingdom

Royal Devon and Exeter Hospital

Barrack Rd
Exeter
EX2 5DW
United Kingdom

Royal Oldham Hospital

Rochdale Rd
Oldham
OL1 2JH
United Kingdom

St Peter's Hospital

Guildford Rd
Lyne
Chertsey
KT16 0PZ
United Kingdom

Stoke Mandeville Hospital

Mandeville Rd
Aylesbury
HP21 8AL
United Kingdom

Basingstoke and North Hampshire Hospital

Aldermaston Rd
Basingstoke
RG24 9NA
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
IPD sharing plan	The data sharing plans for the current study are unknown and will be made available at a later date.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article		29/11/2022	05/12/2022	Yes	No
Results article		01/12/2023	28/12/2023	Yes	No
Protocol article	protocol	15/04/2020	24/04/2020	Yes	No
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Editorial Notes

28/12/2023: The following changes have been made:
1. Publication reference added.
2. The IRAS number has been added from the reference.
05/12/2022: The following changes have been made:
1. Publication reference added.
2. The final enrolment number has been changed from 169 to 1082 based on the reference.
22/03/2022: Total final enrolment added.
18/03/2022: Contact details updated.
10/02/2022: The intention to publish date has been changed from 31/12/2021 to 01/07/2022.
27/01/2021: The following changes have been made:
1. The scientific contact has been changed and the plain English summary updated accordingly.
2. The intention to publish date has been changed from 28/02/2021 to 31/12/2021.
23/10/2020: The plain English summary was updated to reflect the change to the overall trial end date in 29/07/2020.
05/08/2020: The intention to publish date was changed from 31/08/2020 to 28/02/2021.
29/07/2020: The following changes were made to the trial record:
1. The recruitment resumed.
2. The recruitment end date was changed from 31/05/2020 to 31/08/2020.
3. The overall end date was changed from 30/04/2020 to 28/02/2021.
24/04/2020: The following changes have been made:
1. Due to current public health guidance, recruitment for this study has been paused.
2. Bradford Royal Infirmary, Colchester General Hospital, Derriford Hospital, Gloucestershire Royal Hospital, Great Western Hospital, Medway Maritime Hospital, Norfolk and Norwich University Hospital, Royal Devon and Exeter Hospital, Royal Oldham Hospital, St Peter's Hospital, Stoke Mandeville Hospital and Basingstoke and North Hampshire Hospital have been added to the trial participating centres.
3. The participant information sheet field has been updated.
4. The secondary outcome measures have been updated.
5. The participant exclusion criteria have been changed.
6. The recruitment end date has been changed from 31/08/2020 to 30/04/2020.
7. Publication reference added.
22/03/2019: The condition was updated from "Specialty: Children, Primary sub-specialty: Methodology; UKCRC code/ Disease: Neurological/ Inflammatory diseases of the central nervous system" to "meningitis".