Download FLO-ELA summary for sites - V3 March 2017

Open, multi-centre, randomised controlled trial of cardiac output -guided
haemodynamic therapy compared to usual care in patients undergoing
emergency bowel surgery.
This project is funded by the National Institute for Health Research Health Technology Assessment
programme (project number 15/80/54)
Background – Emergency Laparotomy
burden
High incidence (30,000 cases/yr UK)
X
High mortality (20% @ 90-day in >50yrs)
=
Many lives saved if treatments with modest mortality benefit are
routinely adopted
…though showing modest effect size = very large trial!
Background – candidate treatment
Perioperative cardiac output-guided haemodynamic therapy
MORTALITY:
Risk Ratio
0.86 [0.74-1.00]
Pearse et al. JAMA 2014; 311: 2181-90.
Background – candidate treatment
Perioperative cardiac output-guided haemodynamic therapy
However:
VERY few emergency laparotomy patients studied
Elective
Elective
surgery GDHT
≠ Emergency
Emergency
laparotomy
GDHT?
Critical care
GDHT
Background – current practice,
equipoise?
COM-based GDT
NELA Centre
“other” GDT
NELA:
-Cardiac output monitor in 39%
-Limited evidence base  NOT
an audit standard
FLO-ELA clinician survey 2016:
-137 respondents
-85% willing to randomise
% of cases with GDT
Background – potential trial funding?
“Efficient Study Designs” call:
…particular design features – more rapid conduct, lower costs
or both – but giving sufficiently robust data…
…the use of routinely collected data…
…simple randomised trials… focusing on a limited number of
the most important outcomes…
A unique opportunity?
Indisputable
healthcare need
Prioritisation
by clinicians
and public
(JLA)
Hopeful
intervention
with clinician
equipoise
NELA
FLO-ELA
NIHR HTA Efficient Study
Designs
Delivery
infrastructure:
POM-CTN, NIHR
CRN, trainee
networks
Design
Pragmatic multicentre open randomised trial supported by
data from the ongoing National Emergency Laparotomy Audit
(NELA).
Recruitment support and local monitoring from research
nurses, “real world” intervention delivery by clinicians.
• Inclusion criteria: Patients aged 50+ requiring emergency
bowel surgery in line with NELA criteria – with/without
capacity
• Exclusion criteria: Patient or clinician refusal
Design
• Intervention: cardiac output monitoring to determine the dose &
timing of intravenous fluid administration according to a
suggested algorithm, during and up to six hours after emergency
laparotomy.
Clinician discretion on choice of cardiac output monitor shown to
accurately track stroke volume changes and of isotonic fluid type for
boluses.
• Control group: Intravenous fluid administration without the use
of cardiac output monitoring or algorithm.
Basic standards of care set for both groups
Design
• Primary outcome: mortality 90 days after surgery
• Secondary outcomes: 1-yr mortality, critical care and hospital LoS,
cost effectiveness
• Sample size: 7646 patients (3823 per group) to detect an absolute
reduction in mortality at 90-days from 19% to 16% with 90%
power
• Sites and recruitment: 100 UK sites taking part in NELA,
recruitment over three years from mid 2017.
Efficiencies
• NELA & NHS Digital for all patient and outcome data
• Minimal supplementary data fields to track intervention
• Reduced research staff requirement
• Research active trainees and consultants support recruitment – track
record
• Clinicians deliver intervention – familiarity
• Industry support for intervention costs
Centres and Recruitment
100% of target
80% of target
Total centres open
10000
120
9603
9000
100
Patients recruited
8000
7682
7000
80
6000
5000
60
4000
40
3000
2000
20
1000
0
0
0
5
10
15
20
25
Recruitment month
30
35
40
Key challenges 1: delivering
recruitment
• Lots of eligible patients (~25,000/yr across NELA)
• Within 100 of 192 NELA centres, recruiting 30% of this
group for 3yrs = sample size achieved
• Strong track record:
•
•
•
•
EPOCH as “NELA + trial” model
OPTIMISE as large contemporary GDHT trial
Trainees as capable of supporting / delivering RCTs
Recruiting critically ill patients +/- capacity at all hours to large RCTs
• POM-CTN adoption & NELA network to engage local teams
Key challenges 2: protocol
compliance
• Vital to maintain separation between
control/intervention group despite pragmatic
design
• Individual clinician equipoise a prerequisite to
randomisation
• Monitoring, feedback and management of
protocol adherence / contamination – including
removal of sites with poor compliance rates
Managing the risk – feasibility
phase
• First year of recruitment to look at:
Sites opening, recruitment rates, adherence and
contamination
• Targets:
• 90-100 sites open and recruiting
• >80% of predicted recruitment
• <10% protocol deviations
FLO-ELA local Principal Investigators –
key roles
• Champion to clinical teams
• Gather a team covering surgery, anaesthesia, critical care
• Establish working practices – trainees and front line on call teams
– round the clock recruitment
• Encourage equipoise
• Support rapid site set-up
• Recruit average 3-4 patients per site per month when established
(2-3 in hours, 1-2 out of hours)
• Ensure protocol compliance
Support for participating centres
• Funded research nurse time
• NIHR Portfolio Band 3 tariff
• Support from industry
• Simple design – non-CTIMP, no extensive intervention or complex
outcomes follow-up for research team
Conclusion
• An exciting and unique opportunity to guide clinical
practice on a key intervention
• Large pragmatic design – great community and
network support is vital
• Watch this space!
@FLOELAtrial
Chief Investigator: Mark Edwards (Consultant in Anaesthesia &
Perioperative Medicine, Honorary Senior Clinical Lecturer, Southampton)
[email protected] - @dr_mark_edwards
Senior Co-investigators: Mike Grocott, Rupert Pearse
Trial team: Monty Mythen, Dion Morton, NELA team (Dave Murray and Iain
Anderson), QMUL Pragmatic Clinical Trials Unit (Brennan Kahan, Anita Patel
(Health Ec), Ann Thomson), Trainee networks (Ben Harris, Marianne
Johnstone), Keith Young (lay representative)