Primary objectiveTo assess whether prevention of aspiration, infections, and fever with metoclopramide, ceftriaxone, paracetamol, or any combination of these in the first 4 days after stroke onset improves functional outcome at 90 days in elderly…
ID
Source
Brief title
Condition
- Body temperature conditions
- Bacterial infectious disorders
- Central nervous system vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome measure is the score on the modified Rankin Scale (mRS) at
90 days (± 14 days), as analysed with multiple regression.
Secondary outcome
At 7 days (± 1 day) or at discharge, if earlier:
- Infections in the first 7 days (± 1 day; frequency, type, and C. difficile
overgrowth syndrome). Infections will be categorised as diagnosed by the
clinician, and as judged by an independent adjudication committee (masked to
treatment allocation);
- 3rd generation cephalosporin resistance in the first 7 days (± 1 day),
detected as part of routine clinical practice;
- Antimicrobial use during the first 7 days (± 1 day), converted to units of
defined daily doses according to the classification of the WHO Anatomical
Therapeutic Chemical Classification System with Defined Daily Doses Index;
- In a subgroup of patients: presence of Extended-Spectrum Beta-Lactamase
(ESBL)-producing bacteria as detected by PCR in a rectal swab.
At 90 days (± 14 days):
- Death;
- Unfavourable functional outcome, defined as mRS 3 to 6;
- Disability assessed with the score on the Barthel Index (BI);
- Cognition assessed with the Montreal Cognitive Assessment (MoCA);
- Quality of life assessed with the EuroQol 5D-5L (EQ-5D-5L);
- Home time: duration of stay in the patient*s own home or a relative*s home
over the first 90 days;
- Patient location over first 90 days (± 14 days): hospital; rehabilitation
service; chronic nursing facility; home.
- SAEs in the 7 days.
Background summary
Every year, 1.3 million Europeans have a first stroke. One fifth to one third
of stroke patients die in the first month after stroke, and one third remain
dependent on the help of others. The annual costs for stroke care in Europe
have been estimated at ¤64.1 billion. Stroke incidence increases almost
exponentially with age, and the personal, societal, and economic burden of
stroke is therefore largely driven by its frequent occurrence in the elderly.
Elderly patients are at the highest risk of complications after stroke, such as
infections and fever. These complications are strongly and independently
associated with a higher risk of death or dependency. The risk of developing
these complications can be reduced by very simple, safe, and cheap measures,
such as metoclopramide for the management of dysphagia, antibiotics for the
prevention of infections, and paracetamol for the prevention of fever, but it
is uncertain whether these measures also improve functional outcome.
Study objective
Primary objective
To assess whether prevention of aspiration, infections, and fever with
metoclopramide, ceftriaxone, paracetamol, or any combination of these in the
first 4 days after stroke onset improves functional outcome at 90 days in
elderly patients with acute stroke.
Secondary objective
- To assess the effect of prevention of infections and fever in the first days
after stroke onset with metoclopramide, ceftriaxone, paracetamol, or any
combination of these, on the following outcomes at 90 days: death, death or
dependency, quality of life, cognition, costs
- To detect specific populations classified by age, sex, stroke severity, body
temperature, co-morbidities, and geographic region, in which the proposed
treatments are particularly effective or not effective.
- To assess the effects of prophylactic treatment with ceftriaxone on
antimicrobial resistance and the occurrence of infections with Clostridium
difficile.
Study design
International, multi-centre, multi-factorial, randomised, controlled,
open-label clinical trial with blinded outcome assessment (PROBE) of
metoclopramide, ceftriaxone, paracetamol, or any combination of these, in 3800
elderly patients with acute ischaemic stroke or intracerebral haemorrhage. The
trial will be performed according to ICH-GCP principles, the Declaration of
Helsinki as most recently amended in 2013, and national and international
regulatory requirements.
Intervention
Patients will be randomly allocated in a 2*2*2 factorial design to any
combination of open-label oral, rectal, or intravenous metoclopramide (10 mg
thrice daily), intravenous ceftriaxone (2000 mg once daily), oral, rectal, or
intravenous paracetamol (1000 mg four times daily), or usual care, started
within 24 hours after symptom onset and continued for 4 days or until complete
recovery or discharge from hospital, if earlier. In patients with moderate to
severe renal impairment or with severe hepatic impairment, the dose of
metoclopramide is reduced to 5 mg thrice daily, and in patients with end-stage
renal disease to 2.5 mg thrice daily. Allocation will be based on proportional
minimisation through a web-based allocation service. Investigators will have
the opportunity to censor a single specific randomisation arm in a specific
patient before randomisation, for example in case of an allergy to one of the
interventions.
Study burden and risks
About half of all patients develop complications after stroke, including
infections and fever. Advanced age and pre-existing co-morbidities increase the
risk of developing these events. In addition, patients with severe, disabling
strokes are particularly vulnerable. These complications can impede functional
recovery, prolong hospital admissions, and are independently associated with an
increased risk of death or long-term dependency. Earlier trials have suggested
that the prevention of these complications may improve outcomes after stroke.
The medication tested in PRECIOUS has been used for decades in patients with
acute stroke to treat nausea and vomiting (metoclopramide), infections
(ceftriaxone), and fever (paracetamol). Serious side effects of these drugs are
uncommon when used according to their marketing authorisations. Their use in
clinical trials on the prevention of complications in patients with acute
stroke was safe and not associated with an increase in serious adverse events
(SAEs). According to the Dutch NFU guideline, the risk associated with
participation in this study is therefore small. Given the potential benefit of
the prevention of complications to the included subjects, future stroke
patients, their caregivers, and society on the one hand and the limited risks
to trial subjects on the other hand, the trial*s Steering Committee and Ethics
Advisory board conclude on a risk-benefit balance strongly in favour of
conducting this clinical trial.
Heidelberglaan 100
Utrecht 3584CX
NL
Heidelberglaan 100
Utrecht 3584CX
NL
Listed location countries
Age
Inclusion criteria
1. A clinical diagnosis of acute ischaemic stroke or intracerebral haemorrhage,
confirmed with CT or MRI scan. A normal CT scan is considered compatible with
ischaemic stroke;
2. A score on the National Institutes of Health Stroke Scale (NIHSS) * 6,
indicating moderately severe to severe stroke;
3. Age 66 years or older;
4. The possibility to start treatment within 24 hours of symptom onset;
5. Written informed consent.
Exclusion criteria
1. Active infection requiring antibiotic treatment, as judged by the treating
physician;
2. Pre-stroke score on the mRS (modified Rankin Scale) *4
3. Death appearing imminent at the time of assessment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-003179-32-NL |
| ISRCTN | ISRCTN82217627 |
| CCMO | NL54304.041.15 |