Study-protocol PASS-trial V 1.1
06-04-2010
Preventive Antibiotics in Stroke Study
PASS-study
Version 1.1, 06-04-2010
Principal investigators
P.J. Nederkoorn, MD, PhD, Department of Neurology, Academic Medical Center (AMC)
D. van de Beek, MD, PhD, Department of Neurology, AMC; Center of Infection and Immunity
Amsterdam (CINIMA), AMC
Study group
R. J. de Haan, PhD, Department of Clinical Epidemiology and Biostatistics, AMC
M.G.W. Dijkgraaf, PhD, Department of Clinical Epidemiology and Biostatistics, AMC
J.M. Prins, MD, PhD, Department of Infectious Diseases, AMC
L. Spanjaard, MD, PhD, Department of Microbiology, AMC
T. van de Poll, MD, PhD, Center of Infection and Immunity Amsterdam (CINIMA), AMC
D.W.J. Dippel, MD, PhD, Department of Neurology, Erasmus MC
F.H. Vermeij, MD, Department of Neurology, Erasmus MC / Sint Fransiscus Gasthuis
Correspondence to:
W.F. Westendorp, MD, PhD-student, Department of Neurology, AMC
Department of Neurology, H2-235, Academic Medical Center University of Amsterdam
PO Box 22700, 1100 DE Amsterdam, The Netherlands
Trial nurses
I.J. Hooijenga, MSc, Department of Neurology, AMC
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General Study Characteristics
Protocol ID
Short title
Version
Date
Coordinating investigator/
Steering committee
Multicentre research
per site
Preventive Antibiotics in Stroke Study
PASS
1.1
6 april 2010
D. van de Beek, MD, PhD, Department of Neurology, AMC P.J. Nederkoorn,
MD, PhD, Department of Neurology, Academic Medical Centre (AMC)
D. van de Beek, MD, PhD (AMC)
I.M. Bronner, MD (Flevoziekenhuis Almere)
D.W.J. Dippel, MD, PhD (Erasmus MC Rotterdam)
R. ten Houten, MD, PhD (Medisch Centrum Alkmaar)
L.J. Kapelle, MD, PhD (UMCU)
H. Kerkhoff, MD, PhD (Albert Schweitzer Ziekenhuis Dordrecht)
I.H. Kwa, MD, PhD (Slotervaart Ziekenhuis Amsterdam)
P.J. Nederkoorn, MD, PhD (AMC)
P. Portegies, MD, PhD (Onze Lieve Vrouwe Gasthuis)
S.M. Schade van Westrum , MD, PhD (Martini Ziekenhuis Groningen)
F.H. Vermeij, MD (St Franciscus Gasthuis/EMC Rotterdam)
E.M.S. Visser, MD, PhD(VU MC)
H.C. Weinstein, MD, PhD (SLAZ)
M. Weisfelt, MD, PhD (Kennemer Gasthuis Haarlem)
H.B. Van der Worp, MD, PhD (UMCU)
Sponsor
AMC
Independent physician
R.M.A. Bie, MD, PhD
R.M.debie@amc.uva.nl
020-6921912
AMC, Department of Neurology
None involved
Pharmacy
Signature sheet
Name
Signature
Date
Head of Department of Neurology:
Van Schaik, MD, PhD
(neurologist, AMC)
Coordinating Investigators:
Dr. D. van de Beek, PhD, MD
(neurologist, AMC)
Dr. P. J. Nederkoorn, PhD, MD
(neurologist, AMC)
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
INTRODUCTION AND RATIONALE
OBJECTIVE
STUDYDESIGN
STUDYPOPULATION
4.1
Population (base)
4.2
Inclusion criteria
4.3
Exclusion criteria
4.4
Sample size calculation
TREATMENT OF SUBJECTS AND STANDARD CARE
5.1
Investigational treatment
5.1
Standard Care
INVESTIGATIONAL MEDICINAL PRODUCT
6.1
Name and description of investigational medicinal product
6.2
Rationale for ceftriaxone
6.3
Description and justification of route of administration and dosage
6.4
Dosages, dosage modifications and method of administration
6.5
Preparation and labelling of Investigational Medicinal Product
6.6
Drug accountability
METHODS
7.1
Study parameters/endpoints
7.1.1 Main study parameter/endpoint
7.1.2 Secondary study parameters/endpoints
7.1.3 Antibiotic resistance
7.2
Randomisation, blinding and treatment allocation
7.3
Study procedures
7.4
Withdrawal of individual subjects
7.4.1 Specific criteria for withdrawal
7.5
Replacement of individual subjects after withdrawal
7.6
Follow-up of subjects withdrawn from treatment
7.7
Premature termination of the study
SAFETY REPORTING
8.1
Section 10 WMO event
8.2
Adverse and serious adverse events
8.2.1 Suspected unexpected serious adverse reactions (SUSAR)
8.2.2 Annual safety report
8.3
Follow-up of adverse events
8.4
Data Safety Monitoring Board (DSMB)
8.5
The steering committee
STATISTICAL ANALYSIS
9.1
Descriptive statistics
9.2
Univariate analysis
9.3
Multivariate analysis
9.4
Interim analysis
ETHICAL CONSIDERATIONS
10.1 Regulation statement
10.2 Recruitment and consent
10.3 Objection by minors or incapacitated subjects
10.4 Benefits and risks assessment, group relatedness
10.5 Compensation for injury
10.6 Incentives
7
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10
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11
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11
11
11
12
12
13
13
13
13
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13
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14
15
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11.
12.
ADMINISTRATIVE ASPECTS AND PUBLICATION
11.1 Handling and storage of data and documents
11.2 Coding of and access to data
11.3 Amendments
11.4 Annual progress report
11.5 End of study report
11.6 Public disclosure and publication policy
REFERENCES
22
22
22
22
23
23
24
24
Appendices
I.
Modified Rankin Scale (mRS)
II.
NIHSS
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SUMMARY
Background
Stroke is a leading cause of death worldwide. The only proven effective therapy for patients with
ischemic acute stroke is intravenous thrombolysis with intravenous tissue plasminogen activator (rtPA). A promising area to gain benefit for acute stroke patients is prevention of infection. Infection
has been associated with unfavourable outcome after stroke. There is also increasing evidence for
‘stroke-induced-immunodepression’, an impaired cellular immunity that occurs in patients after
stroke. Ceftriaxone covers the causative organisms of post-stroke infections, and recent studies
suggest that it has neuroprotective properties. This multicentre, randomized trial will evaluate if
preventive use of ceftriaxone will improve functional health outcome in acute stroke patients.
Objective
The main objective of the PASS-trial is to investigate whether preventive use of the antibiotic
ceftriaxone improves functional health outcomes (defined on the modified Rankin Scale) after 3
months in patients with stroke by preventing infection.
Study-design
We will conduct a multi-centre prospective, randomized, open-label, blinded endpoint (PROBE) trial
of standard care and preventive treatment with ceftriaxone as compared to standard care without
ceftriaxone.
Study-population
All adult patients with stroke (both infarction and haemorrhage) with a score  1 on the National
Institutes of Health Stroke Scale (NIHSS) are eligible for the study. We will include patients with a
maximum time of 24 hours after onset of stroke symptoms.
Intervention
We will compare treatment with ceftriaxone 2000 mg, intravenously, 1 time daily, for 4 days, to
avoidance of preventive antibiotic treatment, against a background of optimal medical care.
Main study endpoint
The primary efficacy end point will be functional health at 3-month follow-up, as assessed by the
modified Rankin scale (mRS) dichotomized as a favourable outcome (mRS 0-2) or an unfavourable
outcome (mRS 3-6).
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Nature and extend of the burden
We will not perform extensive examinations in addition to the standard care in acute stroke patients.
The main difference will be comprised by patients being randomized for standard treatment with
ceftriaxone or standard-treatment without ceftriaxone. Ceftriaxone has shown to be safe in
numerous trials, side-effects are known and will be monitored. In addition to this, we hypothesize
that ceftriaxone has a beneficial effect by preventing post-stroke infection.
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1. INTRODUCTION AND RATIONALE
Stroke is a leading cause of death worldwide. In the Netherlands, stroke (ischemic and hemorrhagic)
affects approximately 40,000 persons per year. The incidence of stroke is increasing rapidly because
of the ageing population1. The only proven effective therapy for patients with ischemic acute stroke
is intravenous thrombolysis with intravenous tissue plasminogen activator (r-tPA) 2. The 30-day case
fatality of stroke rate varies between 15 and 25% and the rate of patients with poor outcome
remains unacceptably high (50%)
1, 2
. The annual costs of stroke are high. In high-income countries,
stroke ranks second after ischemic heart disease from the perspective of costs for society 1. Mean
lifetime costs after stroke have been estimated between 38,000 and 133,000 euro per person. Half of
these costs concerns (nursing) care. New cost-effective acute stroke therapies are warranted. A
promising area to gain benefit for acute stroke patients (both ischemic and haemorrhagic) is
prevention of infection. Infection has been associated with unfavourable outcome after stroke
3, 4
.
This association is also present in patients admitted on a stroke-unit (medium) care with frequent
monitoring and early start of treatment if infection is suspected. Pneumonia is the most common
infection complicating acute stroke. Patients with acute neurological deficit and swallowing
disturbances are at high risk to develop pneumonia in the first days after onset of symptoms. Urinary
tract infection is the second most common infection and may lead to severe systemic illness 4. There
is also increasing evidence for ‘stroke-induced-immunodepression’, an impaired cellular immunity
that occurs in patients after stroke 3. Ceftriaxone is an off-patent antibiotic with broad action against
causative bacteria of infection after acute stroke 5. Recent studies suggested that ceftriaxone also has
neuroprotective properties. In a rat model of ischemic stroke, ceftriaxone reduced mortality and
neurological deficits6. Neuronal survival was improved within the penumbra and ceftriaxone led to
an up regulation of neurotrophins in the peri-infarct zone6. The combination of an effective antibiotic
and neuroprotective agent makes ceftriaxone a highly interesting drug for the proposed clinical trial.
Infections can be prevented by the use of preventive antibiotics in acute stroke. We performed a
meta-analysis of 4 trials on preventive antibiotics in acute stroke, including 426 patients 7. The
proportion of patients with infection was significantly smaller in the antibiotic group than in the
placebo/control group (32/136 [23.5%] versus 53/139 [38.1%]). The pooled odds ratio on infection
was 0.44 (95% confidence interval, 0.23 to 0.86). The use of preventive antibiotics was not associated
with a significant reduction in death. We found no major harm or toxicity. The studies were small,
heterogeneous, and did not primarily investigate clinical outcome. Current international and national
guidelines do not recommend routine preventive antibiotic treatment in stroke patients8, 9. However,
the observed effect in this meta-analysis warrants evaluation of preventive antibiotics in new stroke
trials, using functional clinical outcomes. The aim of the proposed study is to investigate whether
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preventive use of the antibiotic ceftriaxone improves functional health outcomes in patients with
stroke by preventing infection. This will be done in a large multi-centre randomized controlled trial.
Within this trial we will also assess the cost-effectiveness of this preventive treatment.
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2. OBJECTIVE
The main objective of PASS is to investigate whether preventive use of the antibiotic ceftriaxone
improves functional health outcomes (defined on the modified Rankin Scale, Appendix I) after 3
months in patients with stroke by preventing infection.
3. STUDYDESIGN
We will conduct a multi-centre prospective, randomized, open-label, blinded endpoint (PROBE) trial
of standard care and preventive treatment with ceftriaxone as compared to standard care without
ceftriaxone. A theoretical superior design would be a double-blind, placebo-controlled clinical trial.
However, advantages of an open design are lower costs and greater similarity to standard clinical
practice. Moreover, by using open-label therapy, antibiotic intervention can be clinically adjusted in
case of clinical suspicion of infection. Because previous antibiotic treatment has a decisive impact on
the antibiotic choice, management of infections would be more complicated in a double-blind
setting. Naturally, blinding is lost here but only as to treatment. Blinding is maintained regarding the
assessments of the primary outcome, and the majority of the secondary endpoints. The PROBE
design has the additional advantage that the effect of treatment will be tested as it will be provided
in clinical practice.
4. STUDYPOPULATION
4.1 Population (base)
All adult patients with stroke (both infarction and haemorrhage) with a score  1 on the National
Institutes of Health Stroke Scale (NIHSS, appendix II) are eligible for the study.
4.2 Inclusion criteria
1. Age  18 yr
2. Stroke (ischemic and haemorrhagic)
3. Any measurable neurological deficit defined as NIHSS  1
4. Stroke onset < 24 hours
5. Admission
4.3 Exclusion criteria
1. Symptoms or signs of infection on admission requiring antibiotic therapy
2. Use of antibiotics < 24 h before admission
3. Pregnancy
4. Hypersensitivity for cephalosporin
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5. Previous anaphylaxis for penicillin or penicillin-derivates
6. Subarachnoid haemorrhage
Table 1. Sample-size
Centre, local investigator
Estimated number
of patients
AMC Amsterdam (Dr. Nederkoorn, Dr. Van de Beek)
125
Erasmus MC Rotterdam (Dr. Dippel, Drs. Vermeij)
125
Sint Franciscus Gasthuis Rotterdam (Drs. Vermeij)
100
Medisch Centrum Alkmaar (Dr. Ten Houten)
100
Onze Lieve Vrouwe Gasthuis Amsterdam (Prof. Dr. Portegies)
125
Slotervaart Ziekenhuis Amsterdam (Dr. Kwa)
50
Lucas Andreas Ziekenhuis Amsterdam (Dr. Weinstein)
100
Kennemer Gasthuis Haarlem (Dr. Weisfelt)
100
Flevoziekenhuis Almere (Dr. Bronner)
50
Albert Schweitzer Ziekenhuis Dordrecht (Dr. Kerkhoff)
100
Martini Ziekenhuis Groningen (Dr. Schade van Westrum)
80
VU Medical Center Amsterdam (Dr. Visser)
100
UMC Utrecht (Prof.Dr. Kappelle, Dr. Van der Worp)
follows
Total estimated number of patients per year from recruited centres
1155
4.4 Sample-size calculation
It is expected that 50% of the included stroke patients will have an unfavourable health outcome
(Rankin scores 3-6, including death). Calculation of the required sample size is made based on the
assumption that ceftriaxone will reduce the proportion of patients with an unfavourable outcome
from 50 to 45%. A two group Chi-square test with a 0.05 two-sided significance level will have 80%
power to detect the difference between a standard care proportion of 0.50 and a treatment group
proportion of 0.45 (odds ratio of 0.818) when the sample size in each group is 1565. Although we
expect that all (or at least a very high proportion of the) included patients will be available for
evaluation at the end of the study, we intend to enrol 1600 patients per treatment arm: 3200
patients in total. The study will be carried out in the Netherlands. The centres shown below have
already confirmed cooperation and have estimated the number of patients they will include per year.
The numbers represent approximately 50% of the eligible stroke patients in each centre. We
continue approaching centres and we expect to recruit at least 20 centres enabling inclusion of at
least 1500 patients per year. In a conservative estimate we will enrol at least 1000 patients per year.
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5. TREATMENT OF SUBJECTS AND STANDARD CARE
5.1 Investigational treatment
After baseline assessment and informed consent patients will be randomized to receive either:
-
ceftriaxone 2000 mg, intravenously, 1 time daily, for 4 days, started within 24 hours of stroke
onset and standard care, or
-
standard care without preventive ceftriaxone
5.2 Standard care
All patients participating in this study will be admitted to a stroke unit and treated according to the
local standard care at the acute stroke units. If patients will be discharged before day 3 after
admission, study medication will be stopped. If the treating physician decides to withdraw active
treatment in a patient with a very poor prognosis, study medication will also be stopped. The
decision whether patients need treatment with (additional) antimicrobial therapy will be made by
the treating physician. Recommendations for the treatment of infections will be made according to
the Dutch SWAB guidelines for antibiotic policy.
6. INVESTIGATIONAL MEDICINAL PRODUCT
6.1 Name and description of investigational medicinal product
Ceftriaxone, a registered, off-trade, third generation cephalosporin/beta-lactam antibiotic (See SPC
ceftriaxone, section D).
6.2 Rationale for ceftriaxone
To prevent infections, the antimicrobial spectrum should cover most common causative bacteria of
pneumonia and urinary tract infections. Streptococcus pneumoniae, Haemophilus influenzae,
Staphylococcus aureus and Enterobacteriaceae predominate in patients with aspiration pneumonia
that occur within 4 days after admission (community-acquired aspiration syndrome) 10. The most
common causative bacteria of urinary tract infections are Escherichia Coli and other
Enterobacteriaceae 11. Ceftriaxone, a third generation cephalosporin and beta-lactam antibiotic, is
an off-patent antibiotic with a broad action against causative bacteria of infection after acute stroke.
Antibiotics after acute stroke can be used to prevent infection but may also offer neuroprotection.
Ceftriaxone has such neuroprotective action 6, 12, 13. In a rat model of ischemic stroke, administration
of ceftriaxone resulted in reduced mortality and neurological deficits 6. Neuronal survival was
improved within the penumbra and ceftriaxone led to an upregulation of neurotrophins in the periinfarct zone.
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Ceftriaxone has a favourable safety profile. Treatment with ceftriaxone has shown to be safe in
numerous trials and patient series and most side-effects are minor without clinical consequences 5.
Nevertheless, serious adverse effects can occur and will be reported to the data monitoring and
safety committee. Serious adverse events of ceftriaxone that will be recorded are:
-
Clostridium difficile infection (pseudo-membranous colitis)
-
severe allergic reactions, toxic epidermolysis, syndrome of Stevens-Johnson or erythema
multiforme
-
pancreatitis (in patients with risk factors for forming of biliary sludge or stasis)
The minor side-effects of ceftriaxone that have been reported and will be recorded are:
-
superinfection with non-sensitive micro-organisms
-
phlebitis after intravenous use
-
elevated liver enzymes (alanine aminotransferase, aspartate transaminase, alkaline
phosphatase) (recorded on clinical suspicion)
-
oliguria, elevated serum creatinin (recorded on clinical suspicion)
One of the issues to address is increasing antibiotic resistance due to increase of antibiotic usage. In a
previous phase II trial evaluating antibiotic prophylaxis in patients with acute stroke, no difference
was found in antibiotic resistance patterns between treatment and placebo groups 15. Nevertheless,
increasing use of antibiotics will lead to increasing resistance rates
14
. The potential benefit for
individual patients and the growing burden of antimicrobial resistance should be carefully weighted
(see chapter 7.1.3 antibiotic resistance) .
6.3 Description and justification of route of administration and dosage
The study medication will be administered intravenously. Patients will receive 2000 mg of
Ceftriaxone, 1 time daily, for 4 days.
6.4 Dosages, dosage modifications and method of administration
To ensure that sufficient central nervous system ceftriaxone levels are reached we will use a dose of
2000 mg/d, which is comparable with the dosage used in serious infections such as bacterial
meningitis7, 17. Dosage will not be changed during the study. In patients with a Glomerular Filtration
Rate which is equally to or lower than 10ml/min this dosis is allowed (See SPC ceftriaxone, section D).
The medication will be administered intravenously in minimum time of 30 minutes. An inserted ivcanule will stay in place during the 4 days of therapy, in order to minimize discomfort for the patient.
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6.5 Preparation and labelling of Investigational Medicinal Product
No special preparation or labelling procedures will be perfomed.
6.6 Drug accountability
Ceftriaxone is registered in The Netherlands, available on prescription and widely used in different
hospitals. Each participating hospital will ensure the availability of ceftriaxone in their pharmacy.
7. METHODS
7.1
Study parameters/endpoints
7.1.1
Main study parameter/endpoint
The primary efficacy end point will be functional health at 3-month follow-up, as assessed by the
modified Rankin scale (mRS) dichotomized as a favourable outcome (mRS 0-2) or an unfavourable
outcome (mRS 3-6). The proportional odds model provides additional information from ordinal
outcome data, as it takes into account improvements at any point on the mRS 15. Therefore, we will
use this method in a secondary analysis of the primary endpoint. Beneficial effects on this outcome
should be accompanied by effects on the classic endpoints in the same direction to be considered
convincing.
7.1.2
Secondary study endpoints
Our secondary outcomes are:
- Death rate at discharge and at 3 months
- Infection rate during hospital admission,
- Length of hospital admission
- Volume of post-stroke care
- Use of antibiotics during 3 months follow-up
- Functional health using the full ordinal scoring range of the mRS
- Quality adjusted life years (QALYs)
- Costs
7.1.3
Antibiotic resistance
One of the issues to address is increasing antibiotic resistance due to increase of antibiotic use. In a
previous phase II trial evaluating antibiotic prophylaxis in patients with acute stroke, no difference
was found in antibiotic resistance patterns between treatment and placebo groups15. Nevertheless,
increasing use of antibiotics may lead to increasing resistance rates 14.
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Regarding the use of ceftriaxone in this study, the most important issue to address is the increase of
bacteria (mostly Enterobacteriaceae) capable of forming extended-spectrum-bèta-lactamase (ESBL).
ESBL is an enzyme which hydrolyzes bèta-lactam antibiotics by which they become ineffective. In the
Netherlands, rates of ESBL-producing bacteria are rising and estimates of prevalence of E. Coli
resistant to 3rd generation cephalosporin’s in the general population are reported from 1-5%, and K.
Pneumoniae 5-10%16, 17.
In our study, we want to monitor a possible change in prevalence to 10% for E.Coli, and to 15% for K.
Pneumoniae. We will therefore perform analyses in a subgroup of patients on stool cultures,
obtained on day 0, day 7 and after 3 months. A two group Chi2 test with a 0,050 two-sided
significance level will have 80% power to detect this possible change in our study-population (odds
ratio of 2,176) when the sample size in each group is 278. We will therefore perform this subanalysis
on 556 patients. Patients will be consecutively drawn from selected centres and diagnostic
procedures will be performed centrally.
Results of this subanalysis will be interpreted in the light of the growing burden of antimicrobial
resistance and carefully weighted with regard to the potential benefit for individual patients.
7.2
Randomisation, blinding and treatment allocation
We will conduct a prospective, randomized, open-label, blinded-endpoint trial (rationale for this
design is explained in Section 6, study-design). Blinding is lost in our study, but only as to treatment.
The randomisation procedure will be website-based, using permuted blocks and stratified by study
centre, stroke type and stroke severity. Only after registration in the database treatment allocation
can be performed and from this moment it will not be possible to remove patients from the
database. The online randomisation procedure will be made available by the clinical research unit
(CRU) of the AMC. Information regarding the treatment allocation will be kept separate from the
study database. Patient and treating physician will be aware of the treatment allocation however,
the trial research group (including the assessors of outcome) won’t be aware of the allocation. A trial
statistician will report unblinded data to the DSMB for interimanalyses. The steering committee will
be kept unaware of results of interimanalyses unless necessary (see DSMB and Interimanalysis) and
the code will not be broken until the last patients have completed 3 months of follow-up.
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Table 2: investigations and measurements in PASS
Baseline
Discharge/
3 months
2 weeks
Patient characteristics
-
Age, gender
X
-
Ethnicity
X
-
Medical history
X
-
Pre-stroke medication
X
-
Pre-stroke score on mRS
X
-
Screening dysphagia
X
Physical examination
Vital signs
X
Glasgow Coma Scale
X
NIHSS
X
X
Modified Rankin Scale
X
Laboratory, microbiology, radiology examinations in standard care from which data will be collected
Chest X-ray
X
CT-brain
X
Blood sample
X
X
X
Sputum culture
X
Urine-analysis & culture
X
Additional examinations in PASS
Urine-analysis & culture
X
Other
Use of antibiotics 3 months post-stroke
X
Volume of post-stroke care, length of
X
hospital stay (LOS)
7.3
Study procedures
The investigations and measurements in the PASS-trial are shown in table 2. At baseline, patient
history will be recorded and physical examination performed. According to standard care in acute
stroke patients18, 19, a bloodsample will be drawn and a chest X-ray will be performed, from which we
will collect the results. Since these examinations are part of standard care, there is no extra radiation
burden or additional burden otherwise for the patient. One procedure will be performed in addition
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to standard care for studypurpose: a urine analysis and culture. Patients with an infection on
admission will be excluded from the study. Diagnosis of infection on admission will be made by the
treating physician, and is pragmatically defined as signs or symptoms of infection requiring antibiotic
therapy. At discharge, or after 2 weeks, we will record data on infection as secondary endpoint in
twofold. First, according to the treating physician, who will register whether pneumonia, a urinary
tract infection, or another infection was diagnosed in the clinical setting. Secondly, according to
judgement of two experienced infectious disease specialist, blinded for treatment allocation, using
modified criteria of the U.S. Centres for Disease Control and Prevention (CDC) 19. For this purpose, we
will collect data on the diagnostic procedures in patients with “clinical infection” during the first 2
weeks of admission. Recommendations for these procedures in are: a chest X-ray, 2 blood cultures,
urine-analysis and urine culture, a sputum culture, and leukocyte-count and C-reactive protein from
a venous blood sample. This recommendation is based on standard procedures in identifying a focus
of infection in post-stroke care and therefore no additional burden to the patient
18, 19
. In patients
with diarrhoea, faeces will be tested for C. difficile toxin. After 3 months a structured interview by
telephone will be performed in order to assess the primary outcome, expressed in modified Rankin
Scale. A short questionnaire will be sent regarding the amount of post-stroke care, and patients will
be asked to return this to the study-centre.
7.4
Withdrawal of individual subjects
Subjects can leave the study at any time for any reason if they wish to do so without any
consequences. The investigator can decide to withdraw a subject from the study for urgent medical
reasons.
7.4.1
Specific criteria for withdrawal
If patients will be discharged before day 3 after admission, study medication will be stopped. If the
treating physician decides to withdraw active treatment in a patient with a very poor prognosis,
study medication will also be stopped.
7.5
Replacement of individual subjects after withdrawal
We will not replace individual subjects after withdrawal. Our analysis will be according to the
Intention-to-treat-principle and exclusion of these patients would lead to a selective patient sample.
7.6
Follow-up of subjects withdrawn from treatment
The reason for withdrawal of each patient will be recorded: further treatment and policy will be
performed by the treating physician.
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7.7
Premature termination of the study
The Data Safety Monitoring Board can advise the steering committee (see chapter 8.5) to end the
study early (see chapter 8.2 DSMB and chapter 9.1 interim analyses).
8. SAFETY REPORTING
8.1
Section 10 WMO event
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects and
the reviewing accredited METC if anything occurs, on the basis of which it appears that the
disadvantages of participation may be significantly greater than was foreseen in the research
proposal. The study will be suspended pending further review by the accredited METC, except
insofar as suspension would jeopardise the subjects’ health. The investigator will take care that all
subjects are kept informed.
8.2
Adverse and serious adverse events
Adverse events are defined as any undesirable experience occurring to a subject during a clinical
trial, whether or not considered related to the investigational drug. All adverse events reported
spontaneously by the subject or observed by the investigator or his staff will be recorded.
A serious adverse event is any untoward medical occurrence or effect that at any dose
-
results in death;
-
is life threatening (at the time of the event);
-
requires hospitalisation or prolongation of existing inpatients’ hospitalisation;
-
results in persistent or significant disability or incapacity;
-
is a new event of the trial likely to affect the safety of the subjects, such as an unexpected
outcome of an adverse reaction, lack of efficacy of an IMP used for the treatment of a life
threatening disease, major safety finding from a newly completed animal study, etc.
All SAEs will be reported through the web portal ToetsingOnline to the accredited METC that
approved the protocol, within 15 days after the sponsor has first knowledge of the serious adverse
reactions. SAEs that result in death or are life threatening should be reported expedited. The
expedited reporting will occur not later than 7 days after the responsible investigator has first
knowledge of the adverse reaction. This is for a preliminary report with another 8 days for
completion of the report.
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8.2.1
Suspected unexpected serious adverse reactions (SUSAR)
Adverse reactions are all untoward and unintended responses to an investigational product related
to any dose administered. Unexpected adverse reactions are adverse reactions, of which the nature,
or severity, is not consistent with the applicable product information (e.g. Investigator’s Brochure for
an unapproved IMP or Summary of Product Characteristics (SPC) for an authorised medicinal
product).
The sponsor will report expedited the following SUSARs to the METC:

SUSARs that have arisen in the clinical trial that was assessed by the METC;

SUSARs that have arisen in other clinical trial of the same sponsor and with the same
medicinal product, and that could have consequences for the safety of the subjects
involved in the clinical trial that was assessed by the METC.
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted once every
half year to the METC. This line-listing provides an overview of all SUSARs from the study medicine,
accompanied by a brief report highlighting the main points of concern.
The sponsor will report expedited all SUSARs to the competent authority, the Medicine Evaluation
Board and the competent authorities in other Member States. The expedited reporting will occur not
later than 15 days after the sponsor has first knowledge of the adverse reactions. For fatal or life
threatening cases the term will be maximal 7 days for a preliminary report with another 8 days for
completion of the report.
8.2.2
Annual safety report
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year throughout
the clinical trial, a safety report to the accredited METC, competent authority, Medicine Evaluation
Board and competent authorities of the concerned Member States.
This safety report consists of:

a list of all suspected (unexpected or expected) serious adverse reactions, along with an
aggregated summary table of all reported serious adverse reactions, ordered by organ
system, per study;

a report concerning the safety of the subjects, consisting of a complete safety analysis
and an evaluation of the balance between the efficacy and the harmfulness of the
medicine under investigation.
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8.3
Follow-up of adverse events
All adverse events will be followed until they have abated, or until a stable situation has been
reached. Depending on the event, follow up may require additional tests or medical procedures as
indicated, and/or referral to the general physician or a medical specialist.
8.4
Data Safety Monitoring Board (DSMB)
The Data Safety Monitoring Board is an independent committee comprised of three trial experts in
neurology, microbiology and statistics. The DSMB will monitor the safety of the trial and perform
interim analyses at regular predetermined intervals. Based on this information they will advise the
steering committee on prespecified grounds, as formulated by the DSMB, to adjust the sample size,
or early terminate the study (see chapter 9.4 interim analyses).
8.5
Data Monitoring
An independent monitor from the CRU will monitor the data. In all trial subjects the informed
consent forms and the in- and exclusion criteria will be checked. Source data verification will be
performed in a sample of the population. The monitor also verifies whether all SAE’s and SUSAR’s are
appropriately reported within the time frames required by GCP, the protocol, the ethics committee,
and the applicable regulatory requirement(s).
8.6
The Steering Committee
The management of the trial will be overseen by the steering committee, composed of two
neurologists with experience in vascular neurology, neurologic infectious diseases, clinical trials and
statistics.
9. STATISTICAL ANALYSIS
9.1
Descriptive statistics
Statistical analysis will be based on the intention-to-treat principle. Baseline assessments and
outcome parameters will be summarized using simple descriptive statistics.
9.2 Main analysis, primary and secondary analysis
The main analysis will focus on a comparison between the trial treatment groups of the primary
outcome, a dichotomized mRS score, expressed in a relative risk (RR) estimate.
The secondary outcome parameters (death rate, infection rate, length of hospital stay, volume of
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post-stroke care, volume of antibiotics, and functional health using the full ordinal scoring range of
the mRS) will be analysed using the Chi-squared test (including RR estimates), two group t-test or
Mann-Whitney test, when appropriate. Finally, we will perform predefined subgroup analyses for
stroke type (infarction or haemorrhage), severe strokes (NIHSS score>7), and the presence of
swallowing disorder. In all analyses statistical uncertainties will be quantified via corresponding 95%
confidence intervals.
9.3 Multivariate analysis
For prognostic modelling we will use multivariate logistic regression on the blinded and pooled data
of both trial treatment groups to estimate the probability of poor outcome (mRS 2-6). The following
risk factors will be entered into the regression model: age, sex, stroke severity (according to the
NIHSS), previous stroke, stroke type (haemorrhagic or ischemic), and diabetes mellitus.
In addition to the primary analysis with a fixed mRS cut point score between ‘favourable’ versus
‘unfavourable’ health outcome, we will perform an analysis without a fixed cut point based on the
concept of ‘proportional odds’. The proportional odds model provides additional information from
ordinal outcome data, as it takes into account improvements at any point on the mRS 16. Therefore,
we will use this method in a secondary analysis of the primary endpoint. Beneficial effects on this
outcome should be accompanied by effects on the classic endpoints in the same direction to be
considered convincing.
9.4
Interim analysis
Interim analysis will be performed by the Data Safety Monitoring Board at regular, predetermined
intervals. During the trial-period, data on major outcome events as SAE’s, SUSAR’s and mortality,
believed to be due to treatment, will be collected from the different participating centres and
delivered to the chairman of the DSMB in a confidential way, along with any other analyses on this
data. With this information, the DSMB will advise the steering committee (see chapter DSMB) if, in
their view, the randomized comparisons of the PASS show “proof beyond reasonable doubt” that
for all patients, a part of all patients, or a subgroup of patients, one particular treatment is indicated
or contra-indicated in terms of a difference in outcome or mortality. The exact determination of
“proof beyond reasonable doubt” will be determined by the members of the DSMB before start of
the study.
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10. ETHICAL CONSIDERATIONS
10.1
Regulation statement
The study will be conducted according to the principles of the Declaration of Helsinki (version of
2004) and in accordance with the Medical Research Involving Human Subjects Act (WMO) and other
guidelines, regulations and Acts. Data management, monitoring and reporting of the study will be
performed in accordance with the ICH GCP guidelines. Technicians and data managers of the AMC
Clinic Research Unit (CRU) will perform central data management using Oracle Clinical. Internetbased remote data capture will be used for entering, managing and validating data from the
investigative sites. Oracle Clinical was designed to meet industry regulations, including:
• FDA 21CFR Part 11 Rule (1997)
• ICH; Good Clinical Practice: Consolidated Guideline (1997)
• FDA Guidance for Industry “Computerized Systems Used In Clinical Trials” (1999)
10.2
Recruitment and consent
When the selection criteria are fulfilled, the patient or, if necessary, the patients representative will
be asked for written informed consent, in accordance with the guidelines of the local medical ethics
committee (METC). When the patient has diminished decision-making capacity as result of the stroke
e.g. due to aphasia or cognitive impairment informed consent will be obtained from the patient’s
representative. Exclusion of these non-communicative stroke patients would lead to a selective
patient sample. Information materials for patients and patients' relatives are attached separately.
10.3
Objection by minors or incapacitated subjects
Not applicable (therapeutic research).
10.4
Benefits and risks assessment, group relatedness
Patients might benefit from this study. Prophylaxis with ceftriaxone has a great potential to
effectively reduce the proportion of patients with poor outcome after acute stroke (see Rationale,
Chapter 1).
10.5
Compensation for injury
The AMC Medical Research BV has a liability insurance which is in accordance with article 7,
subsection 6 of the WMO, as well as an insurance which is in accordance with the legal requirements
in the Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical
Research in Humans of 23th June 2003). This insurance provides cover for damage to research
subjects through injury or death caused by the study.
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1. € 450.000,-- (i.e. four hundred and fifty thousand Euro) for death or injury for each
subject who participates in the Research;
2. € 3.500.000,-- (i.e. three million five hundred thousand Euro) for death or injury for all
subjects who participate in the Research;
3. € 5.000.000,-- (i.e. five million Euro) for the total damage incurred by the organisation for
all damage disclosed by scientific research for the Sponsor as ‘verrichter’ in the meaning
of said Act in each year of insurance coverage.
The insurance applies to the damage that becomes apparent during the study or within 4 years after
the end of the study.
10.6
Incentives
Included patients will not receive any special incentives, compensation or treatment other than
medical treatment with ceftriaxone through participation in this study.
11. ADMINISTRATIVE ASPECTS AND PUBLICATION
11.1
Handling and storage of data and documents
The study will be conducted according to the principles of the Declaration of Helsinki (version of
2004) and in accordance with the Medical Research Involving Human Subjects Act (WMO) and other
guidelines, regulations and Acts. Data management, monitoring and reporting of the study will be
performed in accordance with the ICH GCP guidelines. Technicians and data managers of the AMC
Clinic Research Unit (CRU) will perform central data management using Oracle Clinical. Internetbased remote data capture will be used for entering, managing and validating data from the
investigative sites. Oracle Clinical was designed to meet industry regulations, including:
• FDA 21CFR Part 11 Rule (1997)
• ICH; Good Clinical Practice: Consolidated Guideline (1997)
• FDA Guidance for Industry “Computerized Systems Used In Clinical Trials” (1999)
When the trial is finished, all essential documents (Case Record Forms, Informed Consent forms,
patient files, test reports) will be archived and stored for the next 15 years, in accordance to GCPguidelines.
11.2
Coding of and access to data
Patient’s data are coded with a unique number. This consists of five numbers, in which the first two
numbers indicate the hospital, and the last three the number of inclusion in this centre. The key to
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this code is known in the coordinating research centre, the coordinating researchers and research
team will have entry to this code.
The Data Safety Monitoring Board, the health-inspection, the METC, audits and monitors will have
access to source documents.
11.3
Amendments
A ‘substantial amendment’ is defined as an amendment to the terms of the METC application, or to
the protocol or any other supporting documentation, that is likely to affect to a significant degree:
- the safety or physical or mental integrity of the subjects of the trial;
- the scientific value of the trial;
- the conduct or management of the trial; or
- the quality or safety of any intervention used in the trial.
All substantial amendments will be notified to the METC and to the competent authority.
Non-substantial amendments will not be notified to the accredited METC and the competent
authority, but will be recorded and filed by the sponsor.
11.4
Annual progress report
The investigator will submit a summary of the progress of the trial to the accredited METC once a
year. Information will be provided on the date of inclusion of the first subject, numbers of subjects
included and numbers of subjects that have completed the trial, serious adverse events/ serious
adverse reactions, other problems, and amendments.
11.4
End of study report
The sponsor will notify the accredited METC and the competent authority of the end of the study
within a period of 90 days. The end of the study is defined as the last interview by phone performed
after 3 months follow-up of the last included patient.
In case the study is ended prematurely, the sponsor will notify the accredited METC and the
competent authority within 15 days, including the reasons for the premature termination.
Within one year after the end of the study, the investigator/sponsor will submit a final study report
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with the results of the study, including any publications/abstracts of the study, to the accredited
METC and the Competent Authority.
11.5
Public disclosure and publication policy
The coordinating investigators will have the responsibility for decisions regarding publication of data
for scientific purposes.
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12. REFERENCES
1. van der Worp HB, van GJ. Clinical practice. Acute ischemic stroke. N Engl J Med
2007;357(6):572-579.
2. Hacke W, Donnan G, Fieschi C et al. Association of outcome with early stroke treatment:
pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet
2004;363(9411):768-774.
3. Emsley HC, Hopkins SJ. Acute ischaemic stroke and infection: recent and emerging concepts.
Lancet Neurol 2008;7(4):341-353.
4. Vermeij FH, Scholte op Reimer WJ, de MP et al. Stroke-associated infection is an independent
risk factor for poor outcome after acute ischemic stroke: data from the Netherlands Stroke
Survey. Cerebrovasc Dis 2009;27(5):465-471.
5. Lamb HM, Ormrod D, Scott LJ, Figgitt DP. Ceftriaxone: an update of its use in the
management of community-acquired and nosocomial infections. Drugs 2002;62(7):10411089.
6. Thone-Reineke C, Neumann C, Namsolleck P et al. The beta-lactam antibiotic, ceftriaxone,
dramatically improves survival, increases glutamate uptake and induces neurotrophins in
stroke. J Hypertens 2008;26(12):2426-2435.
7. van de Beek D, Wijdicks EF, Vermeij FH et al. Preventive antibiotics for infections in acute
stroke: a systematic review and meta-analysis. Arch Neurol 2009;66(9):1076-1081.
8. Adams HP, Jr., del ZG, Alberts MJ et al. Guidelines for the early management of adults with
ischemic stroke: a guideline from the American Heart Association/American Stroke
Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and
Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care
Outcomes in Research Interdisciplinary Working Groups: The American Academy of
Neurology affirms the value of this guideline as an educational tool for neurologists.
Circulation 2007;115(20):e478-e534.
9. Nederlandse Vereniging voor Neurologie. Richtlijn diagnostiek, behandeling en zorg voor
patiënten met een beroerte 2009. 2009.
10. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 2001;344(9):665671.
11. Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Engl J Med
1993;329(18):1328-1334.
- 25 -
Study-protocol PASS-trial V 1.1
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12. Lee SG, Su ZZ, Emdad L et al. Mechanism of ceftriaxone induction of excitatory amino acid
transporter-2 expression and glutamate uptake in primary human astrocytes. J Biol Chem
2008;283(19):13116-13123.
13. Lipski J, Wan CK, Bai JZ, Pi R, Li D, Donnelly D. Neuroprotective potential of ceftriaxone in in
vitro models of stroke. Neuroscience 2007;146(2):617-629.
14. Hawkey PM. The growing burden of antimicrobial resistance. J Antimicrob Chemother
2008;62 Suppl 1:i1-i9.
15. McHugh GS, Butcher I, Steyerberg EW et al. A simulation study evaluating approaches to the
analysis of ordinal outcome data in randomized controlled trials in traumatic brain injury:
results from the IMPACT Project. Clin Trials 2010;7(1):44-57.
16. EARSS. Antimicrobial resistance in Europe. 64. 2010.
17. Livermore DM, Canton R, Gniadkowski M et al. CTX-M: changing the face of ESBLs in Europe.
J Antimicrob Chemother 2007;59(2):165-174.
18. Adams HP, Jr., del ZG, Alberts MJ et al. Guidelines for the early management of adults with
ischemic stroke: a guideline from the American Heart Association/American Stroke
Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and
Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care
Outcomes in Research Interdisciplinary Working Groups: The American Academy of
Neurology affirms the value of this guideline as an educational tool for neurologists.
Circulation 2007;115(20):e478-e534.
19. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated
infection and criteria for specific types of infections in the acute care setting. Am J Infect
Control 2008;36(5):309-332.
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