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Paul Dark - Biomarker guided duration of antibiotic treatment
1. BiomArker-guided Duration of Antibiotic treatment
in hospitalised PaTients with Sepsis
ADAPT-Sepsis Trial Investigators
Biomarkers: Serum Procalcitonin (PCT) & C-reactive protein (CRP)
2. Investigator team
⢠Critical Care: Paul Dark ( Manchester); Gavin Perkins (Warwick); Danny McAuley (Belfast); Tony Gordon
(Imperial); Mervyn Singer (UCL); Tim Walsh (Edinburgh); Gordon Carlson (Salford)
⢠Microbiologists/antibiotic stewardship: Ronan McMullan (Belfast); Peter Wilson (UCL)
⢠Statisticians/trial methodologists: Ranjit Lall; Simon Gates (Warwick)
⢠Health economics: Matt Stephenson (Sheffield)
⢠Patients/relatives: Keith Young (Intensive Care Society/Salford Citizen Scientists)
⢠Laboratory clinical biochemistry: Jonathan Clayton (Salford)
⢠Outcome data linkage: Paul Mouncey (ICNARC); Naz Lone (Edinburgh)
⢠Pharmacology/pharmacy: Tim Felton; Kay Marshall (Manchester)
⢠Trial managers and coordinators: Scott Regan, Nicola McGowan, Johnny Gluck, Maddie Flawn
(Warwick Clinical Trials Unit).
Independent Trial Steering Committee: Chair Julian Bion (Birmingham)
Independent Data Monitoring Committee: Chair Ly-Mee Yu (Oxford)
3. Intended learning outcomes
â˘Identify sepsisas a severe life-threatening infection syndrome
â˘Describe NICEDiagnostic Guidance in sepsis
â˘Outline a NIHR HTA commissioned diagnostic trial
â˘Discuss opportunities for trial adoption at your centre
â˘Discuss knowledge mobilisation from trial into NHS
5. Background
NICE Diagnostic Guidance DG18 (Oct. 2015):
âProcalcitonin testing for diagnosing and monitoring sepsisâ
â˘Systematic review of clinical and cost effectiveness
â˘8 RCTs (critically ill adults with sepsis) = daily PCT for antibiotic
discontinuation
â˘All âuncertain qualityâ with some âat significant risk of biasâ
6. Background
NICE Diagnostic Guidance DG18 (Oct. 2015)
â˘Promising results from international trials
â˘Concerns about risk of performance bias from evidence base
â˘Lack of a systematic evidence from the UK
â˘Uncertainty of results in current standard NHS clinical practice
Further research is recommended in UK
Is there a role for CRP monitoring?
7. Research question
Research Question:
Does a treatment protocol based on serial monitoring of CRP or PCT
safely allow reduction in duration of antibiotic therapy in hospitalised
patients with sepsis?
Specifies: definitive 3-arm RCT
8. Population: Hospitalised adults receiving intravenous
antibiotics for suspected sepsis
Intervention: Antibiotic discontinuation protocol based on
monitoring daily CRP or PCT
Comparator: Standard NHS care for patients with sepsis
Outcomes: Antibiotic duration (effectiveness)
28-day all-cause mortality (safety)
9. Pilot data
1. Antibiotic duration for sepsis in the UK?
⢠No readily available high quality reliable data from UK
⢠International recommendations: 7-10 days (Surviving Sepsis Guidelines)
⢠PHE antibiotic stewardship guidance: 7 days
⢠Best estimate from Evelien de Jong (SAPS trial 2016)
⢠Netherlands (documented low antibiotic burden country)
⢠Median duration 7 (IQR 4-11) days standard care arm
10. Pilot data
2. Is there equipoise in UK for PCT and CRP monitoring in sepsis?
Survey of healthcare professionals managing patients with sepsis
â˘380 contributors over 4 weeks
â˘CRP frequently used non-systematically with no defined stop rules
â˘PCT used infrequently with stop rules consistent with NICE DG 18
â˘High desire to take part in a large scale pragmatic RCT (76%)
50 NHS service laboratories surveyed separately with concordant
Results and important assay platform information for trial feasibility
11. Study design
Multi-centre 3-arm randomised controlled trial
Internal pilot (completed Oct 2018)
Random group allocation
â˘computer-generated randomisation sequence with the
minimisation method using random blocks
â˘randomised in a ratio of 1:1:1 to PCT:CRP: usual care
Stratification by:
â˘centre
â˘severity of sepsis
â˘surgery within 72 hours or not
12. Study design
Inclusion criteria
â˘Age at least 18 years
â˘Hospital inpatient
â˘Commenced on iv antibiotics for sepsis (within 24 hours)
â˘Likely to be receiving intravenous antibiotics at 72 hours
â˘Requires Critical Care
Main exclusion criteria
â˘Prolonged antimicrobial therapy mandated (e.g. for
tuberculosis, osteomyelitis)
â˘Severely immunocompromised (e.g. neutropenia, less than 500
neutrophils/microliter)
13. Study interventions
PCT protocol
Standard care + daily
serum PCT measurement
until antibiotic
discontinuation
CRP protocol
Standard care + daily
serum CRP measurement
until antibiotic
discontinuation
Advice for both PCT and
CRP groups delivered daily
to treating clinician
PCT < 0.25Âľg/l CRP < 25mg/l
âProtocol STRONGLY
supports stopping antibioticsâ
PCT fall by >80% from
baseline or PCT > 0.25 & <
0.50 Âľg/l
CRP fall by 50% from
baseline
âProtocol suggests stopping
antibioticsâ
PCT does not meet above
criteria
CRP does not meet above
criteria
âProtocol supports usual
careâ
14. Study interventions
PCT protocol
Standard care + daily
serum PCT measurement
until antibiotic
discontinuation
CRP protocol
Standard care + daily
serum CRP measurement
until antibiotic
discontinuation
Advice for both PCT and
CRP groups delivered daily
to treating clinician
Control group advice
delivered daily to
treating clinician
PCT < 0.25Âľg/l CRP < 25mg/l
âProtocol STRONGLY
supports stopping antibioticsâ
âProtocol supports usual
careâ
PCT fall by >80% from
baseline or PCT > 0.25 & <
0.50 Âľg/l
CRP fall by 50% from
baseline
âProtocol suggests stopping
antibioticsâ
âProtocol supports usual
careâ
PCT does not meet above
criteria
CRP does not meet above
criteria
âProtocol supports usual
careâ
âProtocol supports usual
careâ
20. Study design
Primary outcome measures:
1. Effectiveness
â˘Total duration of antibiotic treatment to 28 days following
randomisation (superiority) measured in days (24-hour time
periods from randomisation)
2. Safety
â˘28-day all-cause mortality (non-inferiority) following
randomisation as primary safety outcome
21. Study design
Secondary effectiveness & safety outcome measures to 28 days:
â˘Antibiotic dose (measured as Defined Daily Dose)
â˘Unscheduled care escalation/re-admission
â˘Infection relapse/recurrence requiring further antibiotic treatment
â˘Super-infection defined as new infection at a different anatomical site
All-cause mortality rates at 90 days will be collected via linked records
Health care system benefit measures:
â˘Assessment of in-trial cost effectiveness
â˘Critical care unit length and level of stay
â˘Hospital length of stay
Process evaluation of trial:
22. Study design
A total sample size of 2760 (912 patients per group)
To detect both:
â˘a mean of 1-day reduction in antibiotic duration
(using a mean antibiotic duration of 7 days, a pooled standard
deviation of 6 days, 90% power, a significance level of 5%, with a
5% withdrawals rate)
â˘a non-inferiority safety margin of 5%
(using a 1-sided significance level of 2.5%, 90% power and 5%
withdrawal rate) assuming 28-day mortality is 15%.
24. Intended learning outcomes
â˘Identify sepsis as a severe life-threatening infection syndrome
â˘Describe NICE Diagnostic Guidance in sepsis
â˘Outline an NIHR HTA commissioned diagnostic trial (ADAPT-Sepsis)
â˘Discuss opportunities for NIHR trial adoption at your centre
â˘Discuss knowledge mobilisation from trial into NHS care