Clinical Trial Results:
A cluster randomised trial of different strategies of antibiotic use to reduce the incidence and consequences of chest infection in acute stroke patients with swallowing problems.
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Summary
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EudraCT number |
2007-004298-24 |
Trial protocol |
GB |
Global end of trial date |
18 Sep 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Dec 2018
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First version publication date |
06 Dec 2018
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Other versions |
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Summary report(s) |
FINAL STUDY REPORT |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
KCH-STR-INF
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Additional study identifiers
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ISRCTN number |
ISRCTN37118456 | ||
US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
King's College Hospital
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Sponsor organisation address |
Denmark Hill, London, United Kingdom, SE59RS
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Public contact |
Professor Lalit Kalra, King's College Hospital NHS Foundation Trust, 0044 0203299 1718, lalit.kalra@kcl.ac.uk
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Scientific contact |
Professor Lalit Kalra, King's College Hospital NHS Foundation Trust, 0044 0203299 1718, lalit.kalra@kcl.ac.uk
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Sponsor organisation name |
King's College London
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Sponsor organisation address |
The Strand, London, United Kingdom, WC2R 2LS
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Public contact |
Professor Lalit Kalra, King's College London, 0044 0203299 1718, lalit.kalra@kcl.ac.uk
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Scientific contact |
Professor Lalit Kalra, King's College London, 0044 0203299 1718, lalit.kalra@kcl.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
09 Apr 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
18 Sep 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Sep 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main hypothesis for the study is that prophylactic use of antibiotics (an "act first" approach) in acute stroke patients with swallowing problems on a bedside clinical assessment will be better than the current practice of monitoring for infection and treatment if necessary (a "wait and watch" approach) in reducing chest infections and their consequences in stroke patients
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Protection of trial subjects |
The study will be undertaken in hospital based stroke units that have a defined policy for acute stroke care and participate in the National Stroke Audit (NSA).
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Background therapy |
not applicable | ||
Evidence for comparator |
A Pragmatic cluster randomised controlled trial in 50 participating stroke units. Cluster randomisation at the stroke unit level for treatment or no treatment. | ||
Actual start date of recruitment |
01 Jan 2009
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 1224
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Worldwide total number of subjects |
1224
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EEA total number of subjects |
1224
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
160
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From 65 to 84 years |
678
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85 years and over |
386
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Recruitment
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Recruitment details |
Between April 21, 2008, and May 17, 2014, we randomly assigned 48 stroke units (and 1224 patients clustered within the units) to the two treatment groups: 24 to antibiotics and 24 to standard care alone (control). | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
The inclusion criteria: 1. Ischaemic or hemorrhagic stroke confirmed on CT imaging 2. Recruited within 48 hours of symptom onset 3. Unable to tolerate normal diet or fluids because of a. impaired consciousness levels. b. failed clinical bedside swallowing assessment performed by a trained assessor c. “nil orally” orders, nasogastric tubes, mo | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||
Blinding implementation details |
Cluster-randomised, open-label controlled trial. Centres were randomised on a 1:1 ratio to either the intervention or the control group using a minimisation algorithm. Randomisation was stratified for number of stroke admissions per year and the proportion of admitted directly to specialist care
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Antibiotic Intervention | ||||||||||||||||||||||||
Arm description |
Patients received prophylactic antibiotics for 7 days plus standard stroke unit care | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Amoxicillin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for injection/infusion, Powder and solvent for oral solution
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
Administered according to local practice for 7 days
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Investigational medicinal product name |
Clarithromycin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for concentrate for solution for infusion, Powder for oral solution, Powder for oral solution in sachet, Powder for oral suspension
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Routes of administration |
Intravenous drip use , Oral use
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Dosage and administration details |
Administered according to local policy and care for 7 days
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Investigational medicinal product name |
Metronidazole
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral solution, Powder and solvent for solution for injection/infusion, Oral emulsion
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Routes of administration |
Oral use, Intravenous drip use
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Dosage and administration details |
Administered according to local practice and care for 7 days
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Investigational medicinal product name |
Trimethoprim
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral liquid, Oral solution, Oral suspension, Powder and solvent for solution for infusion
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
Administered according to local practice and care for 7 days
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Arm title
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Control Arm | ||||||||||||||||||||||||
Arm description |
Standard clinical care with no intervention. | ||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
Overall Trial
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Reporting group description |
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End points reporting groups
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Reporting group title |
Antibiotic Intervention
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Reporting group description |
Patients received prophylactic antibiotics for 7 days plus standard stroke unit care | ||
Reporting group title |
Control Arm
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Reporting group description |
Standard clinical care with no intervention. | ||
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End point title |
Clinical Endpoint [1] | |||||||||
End point description |
The clinical primary outcome measure is the incidence of PSP in the first 14 days after stroke onset or prior to discharge home if sooner. This will be defined as temperature >37.5°C on two consecutive measurements or a single measurement of >38.0°C with chest symptoms and one or more of the following: white cell count >11 000/mL, pulmonary infiltrate on chest x-rays, positive microbiology cultures.[2,8-10] The diagnosis of PSP will be adjudicated independently by non-participating clinicians masked to treatment allocation based on anonymised clinical information submitted by centres.
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End point type |
Primary
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End point timeframe |
0 to 90 days post Stroke
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Please see attached document for results. |
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Attachments |
Results SAE LINE LISTING |
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End point title |
Primary Economic Endpoint [2] | |||||||||
End point description |
The primary cost outcome measure will be the total hospital costs (acute and rehabilitation) for the initial episode of care, calculated as a product of costs per unit of each type of care (standardised NHS tariff) and amount used, using methodology validated previously
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End point type |
Primary
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End point timeframe |
Duration of the trial
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Please see attached document for results. |
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Attachments |
Results Lancet |
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End point title |
Death | |||||||||
End point description |
At 14 days:
1. Death, death or PSP at 14 days of stroke onset
2. National Institute of Health Stroke Scale (NIHSS) at 14 days of stroke onset or at discharge if sooner
3. Change in NIHSS from baseline at 14 days of stroke onset or at discharge if sooner
4. Discontinuation of antibiotic prophylaxis in the intervention group (< 4 days of treatment)
5. Antibiotic use in the control group within 7 days of stroke onset
6. Duration of hospital stay if ≤14 days
7. Participation in programmed assessment or therapy activities, measured as the number and duration of supervised rehabilitation during hospital stay.
8. C. difficile diarrhoea
9. New onset of MRSA infection
10. Per protocol Adverse Event (AE), Adverse Reaction (AR), Serious Adverse Event / Reaction (SAE / SAR), and Suspected Unexpected Serious Adverse Reactions (SUSAR).
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End point type |
Secondary
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End point timeframe |
0 to 14 days
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| No statistical analyses for this end point | ||||||||||
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End point title |
Death & Clinical/ Economic endpoints | |||||||||
End point description |
At 90 days:
11. Modified Rankin Scale at 90 (± 14) days post-stroke
12. Patients achieving dichotomised modified Rankin Scale score (mRS 0-2) at 90 (± 14) days post-stroke
13. Ordinal regression analysis of mRS at 90 (± 14) days post stroke
14. Mortality, institutionalisation and mortality or institutionalisation at 90 (± 14) days post stroke
15. Duration of hospital stay if >14 days
16. Incident chest infections between 15-90 days
17. Barthel Index at 90 (± 14) days
18. EUROQOL scores at 90 (± 14) days post stroke.
19. Incremental cost-effectiveness ratios (ICERs) if either the intervention or control approach involves an additional cost alongside an improvement in outcome (ICERs will then represent the cost per 1% reduction in incidence of PSP and/or cost per quality-adjusted life-year (QALY) gained).
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End point type |
Secondary
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End point timeframe |
At 90 days post Stroke
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| No statistical analyses for this end point | ||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
Until 90 day timepoint
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
Antibiotic Intervention
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Reporting group description |
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| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Please see attached document for adverse event descriptions. |
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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05 Sep 2008 |
Addition of co-sponsor. |
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04 Jun 2009 |
Addition to Participant Exclusion Criteria:-
Expected survival <2 weeks under exclusion criteria |
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19 Oct 2009 |
Change to IMP storage conditions
1. Old Text – Page 9
“IMPs must be stored in a temperature controlled environment (oC) with restricted access to unauthorized personnel.”
2. New Text – page 8, exclusion criteria
“IMPs must be stored in a temperature controlled environment (stored according to manufactures instructions) with restricted access to unauthorized personnel.”
Change of PI at one site.
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25 Jan 2010 |
Protocol changes to consent and recruitment procedures:-
1. Old Text – Page 8, Recruitment and Consent Procedures
“If a patient is unable to give written consent because of stroke related deficits such as arm weakness or dysphasia, assent for inclusion will be obtained from the next of kin or relatives. Written consent to support the assent will be sought as soon as the patient is able to provide this consent.”
2. New Text – page 8, Recruitment and Consent Procedures
“In circumstances where the patient can read and understand the information on the patient information sheet but is unable to sign due to stroke related deficits such as arm weakness, a researcher or a witness can attest that any mark they make is their signature to consent. Additionally if the patient is able to understand but is unable make a mark due to stroke deficits, an independent witness can countersign the consent form for patient. This witness can be the researcher.
Addition of 8 new clinical sites and change of PI at one existing site. |
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16 Sep 2011 |
1. The duration of the study has been extended up to June 2013 reflecting the current recruitment rates for the study.
2. References to specific recommended antibiotics have been removed from objectives (1) and replaced with prophylactic antibiotics.
3. Objective (3) stated that we will be measuring functional independence, this is not the case, and therefore the statement has been updated.
4. The original recruitment rates in individual centres of 5.6 patients/centre/ month have not been met because of changes in organistaion of stroke services and limited recruitment over weekends. This has changed to a new recruitment target of 2 patients/ centre/ month over a 24 month period.
5. The 4th exclusion criteria have been updated to include “other antibiotics”.
6. Both the health intervention and IMP section in the protocol have been simplified stating that prophylactic treatment will be initiated in dose, form and route in accordance with local hospital antibiotics and infection control policies. It now also includes the addition of the two IMPs (metronidazole and co-trimoxazole) which have been added as they are the preferred antibiotic regime to be used by Charing Cross Hospital (Imperial College Healthcare NHS Trust).
7. References to chest x-ray have been replaced with a statement to the effect that the treatment for patients with raised temperature will follow normal clinical management, and results will be recorded in the CRF. |
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17 Sep 2014 |
Chest infections have been replaced by Post Stroke Pneumonia (PSP) throughout the protocol
The sample size has been updated to reflect a reduced attrition rate.
The primary endpoint has been changed from chest infection to post stroke pneumonia based on TSC adjudication.
Statistical analysis section of the protocol now provides details of analytical methods.
The following non-substantial changes have also been incorporated into this amendment and these have been included in the submission:
Page 1: Short title added
Change in CI details
Change in trial duration
Page 4: The trial flow has been refined to be clearer, no change in design
Page 5: 2nd paragraph (background) updated
Page 7: Inclusion criteria unchanged but presented more clearly
Page 10: Secondary endpoints reformatted for better visualisation, otherwise unchanged.
Page 15The names of the Chair and members of the TMG, TSC and DMEC have been added.
Page 16 Publication Policy added
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Selection bias, especially in a cluster-randomised trial, could result from patients at increased risk of post-stroke pneumonia being recruited preferentially to the antibiotic intervention group. But no differences noted in baseline characteristics. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/30196790 http://www.ncbi.nlm.nih.gov/pubmed/26343840 |
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