Which previous trials have been performed with metoclopramide?

In the randomised phase II Metoclopramide to prevent Pneumonia in Stroke patients fed via nasogastric tubes (MAPS) trial of the management of dysphagia, 60 patients were randomised to metoclopramide 30 mg daily or placebo within 7 days of stroke onset and within 48 hours of insertion of a nasogastric tube. The trial medication was continued for 21 days or until nasogastric feeds were discontinued. Twenty six (87%) of the patients randomised to placebo and 8 (27%) of the patients randomised to metoclopramide developed pneumonia (adjusted rate ratio, 5.24; 95% CI, 2.43 to 11.27; p<0.001). Twelve (40%) patients in the placebo group and 8 (27%) in the metoclopramide group died within 30 days after start of treatment (adjusted estimate, 1.85; 95% CI, 0.59 to 5.80; p=0.292).46 The trial did not assess the effect of metoclopramide on functional outcome. There were no differences in adverse events (AEs) between the two groups. Oculogyric crises, dystonic reactions, tardive dyskinesia, and galactorrhoea were not observed.

Warusevitane A, Karunatilake D, Sim J, Lally F, Roffe C. Safety and effect of metoclopramide to prevent pneumonia in patients with stroke fed via nasogastric tubes trial. Stroke 2015; 46: 454-460.


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Which previous trials have been performed with antibiotics?

In a Cochrane meta-analysis of five phase II trial testing the effect of the prevention of infections in patients with acute stroke, prophylactic antibiotics reduced the risk of infections from 36% to 22% (RR, 0.58; 95% CI, 0.43 to 0.79) and were associated with a trend towards a reduced risk of dependency: RR, 0.67; 95% CI, 0.32 to 1.43.44

In the recent Preventive Antibiotics in Stroke Study (PASS) not included in this meta-analysis, 2550 patients with acute stroke were randomly assigned to intravenous ceftriaxone at a daily dose of 2 g, given every 24 h intravenously for 4 days, or to standard care. Treatment was started within 24 hours of stroke onset. Preventive ceftriaxone reduced the incidence of infections from 7% to 3% (OR, 0.44; 95% CI, 0.30 to 0.65; p<0·0001), mainly through a reduction in the occurrence of urinary tract infections, but did not have a statistically significant benefit on the incidence of pneumonia (3% vs. 2%; OR, 0.67; 95% CI, 0.39 to 1.15; p=0.18). The low incidence of infections may be explained by the inclusion of patients with a generally mild stroke: the median score on the NIHSS was 5 (IQR, 3 to 9). Preventive ceftriaxone did not have an effect on functional outcomes at 90 days: adjusted common odds ratio, 0.95; 95% CI, 0.82 to 1.09; p=0.46. The benefit of ceftriaxone appeared to be greater in patients aged 75 years or older than in younger patients (OR, 0.85; 95% CI, 0.67 to 1.06), but there was no significant interaction between the age groups. Post-hoc analysis suggested that ceftriaxone reduced the risk of a poor outcome in patients treated with alteplase from 40% to 33% (adjusted OR, 0.77; 95% CI 0.61 to 0.99; p=0·04). Preventive treatment with ceftriaxone was safe. Overgrowth infection with Clostridium difficile occurred in two patients (0.2%) and infection by a ceftriaxone-resistant microorganism in one patient (0.1%) in the ceftriaxone group; both were not observed in the control group.

In the recent multicentre, cluster-randomised, open-label controlled trial with masked endpoint assessment STROKE-INF, 48 stroke units in the UK (and 1224 patients clustered within the units) were randomly assigned to give either prophylactic antibiotics for 7 days plus standard stroke unit care or standard stroke unit care alone. Patients were eligible for participation if they had stroke and dysphagia, and if prophylactic antibiotic treatment could be started within 48 hours of stroke onset. Eleven units and 7 patients withdrew after randomisation, leaving 1217 patients in 37 units for the intention-to-treat analysis (615 patients in the antibiotics group, 602 in control). Both the type and dose of antibiotic at intervention centres conformed to local antibiotic policies. Of the patients in the intervention group, 78% received amoxicillin or co-amoxiclav together with clarithromycin and 2% a cephalosporin. Prophylactic antibiotics did not affect the incidence of algorithm-defined post-stroke pneumonia (13% in the antibiotics group vs 10% in the control group; marginal adjusted OR, 1.21; 95% CI, 0.71 to 2.08). Infections unrelated to post-stroke pneumonia were less frequent in the prophylactic antibiotics group (4% vs 7%; OR, 0.55; 95% CI, 0.32 to 0.92; p=0.02). There were no differences in mortality rates between the treatment groups or in the percentage of patients with good functional outcomes (mRS 0 to 2) but the distribution of mRS scores shifted towards worse outcomes at 90 days in the intervention group (adjusted OR, 1.26; 95% CI, 1.01 to 1.57; p=0.039). Treatment with prophylactic antibiotics was not associated with an increase of serious adverse events. Diarrhoea positive for C. difficile occurred in two patients (<1%) in the antibiotics group and four (<1%) in the control group.

Westendorp WF, Vermeij JD, Zock E et al. The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial. Lancet 2015; 385: 1519-1526.

Kalra L, Irshad S, Hodsoll J et al. Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial. Lancet 2015.


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Since two trials did not find a benefit of preventive antibiotics, what is the reason to include antibiotics in PRECIOUS?

The results of the PASS and STROKE-INF trial do not support a benefit of prophylactic antibiotics in patients with acute stroke. However, several important limitations of these two trials could explain the observed lack of benefit. The PASS trial included patients with on average mild strokes (a median NIHSS of 5) and consequently had a low number of patients with post-stroke infections in the control group. There are several explanations for the lack of benefit of prophylactic antibiotics in STROKE-INF. First, preventive treatment was started late (up to 48 h after stroke onset). Second, a considerable proportion of patients in the treatment group received a limited number of antibiotic doses, while 34% of the patients in the control group received an antibiotic at least once during the first 7 days. Finally, only a small number of patients were randomised per participating centre over an extended period of time; in a cluster-randomized study, this may induce selection bias decreasing the discriminative power.

We therefore think prophylactic antibiotics still hold promise. Importantly, PASS showed that the use of preventive ceftriaxone was safe. Testing ceftriaxone in PRECIOUS is therefore still warranted!


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Which previous trials have been performed with paracetamol?

Prevention of fever has been tested in three small phase II trials50 and in one published, larger phase III trial: the Paracetamol (Acetaminophen) in Stroke (PAIS) trial, a double-blind, placebo-controlled, randomised clinical trial of 1400 patients with acute stroke.45 In PAIS, treatment with paracetamol 6 g daily for three days, started within 12 hours of stroke onset, reduced the risk of subfebrile temperatures or fever at 24 hours of start of treatment from 30% to 15%.39 Patients treated with paracetamol had better functional outcomes as assessed with the mRS at 90 days than those treated with placebo, but this difference was just not statistically significant (adjusted odds ratio (aOR), 1.21; 95% CI, 0.97 to 1.51).45 In a post-hoc analysis of patients with a baseline body temperature of 37 to 39°C, 40% of the patients in the paracetamol group improved beyond expectation compared with 31% in the placebo group (adjusted OR, 1.43; 95% CI, 1.02 to 1.97), but a stratified Mantel-Haenszel test did not formally indicate heterogeneity in the effect of paracetamol (p=0.12). In PAIS, treatment with high-dose paracetamol was safe. Results of the Paracetamol (Acetaminophen) in Stroke trial 2 (PAIS 2) that was terminated prematurely after inclusion of 300 patients, against a target of 1500, are not known yet. The reason for the premature termination was lack of funding.

den Hertog HM, Van der Worp HB, van Gemert HM et al. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial: a multicentre, randomised, placebo-controlled, phase III trial. Lancet Neurol 2009; 8: 434-440.


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What is the design of the clinical trial?

This is an international, multi-centre, multi-factorial, randomised, controlled, open-label clinical trial with blinded outcome assessment (PROBE) of ceftriaxone, paracetamol, and metoclopramide, or any combination of these, in 3800 elderly patients with acute ischaemic stroke or intracerebral haemorrhage. Patients will be recruited in about 80 hospitals in about 9 European countries over a period of about four years. To increase the generalisability of the findings, these countries are proportionally distributed over Europe, and include Estonia, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, and the United Kingdom.


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What is the dose and route of administration of the studies medications?

The dosage and route of administration of the investigational medicinal products will be as follows:     


  • Metoclopramide: Tablet, suppository, or intravenous infusions in a daily dose of 3 times 10 mg for 4 days or until discharge, if earlier.
  • Ceftriaxone: Intravenous infusion in a once-daily dose of 2000 mg for 4 days or until discharge, if earlier.
  • Paracetamol: Tablets, suppositories, or intravenous infusions in a daily dose of 4 times 1000 mg for 4 days or until discharge, if earlier. Paracetamol will only be given intravenously if oral or rectal administration is impossible, impractical, or refused by the patient.

Treatment needs to be started within 12 hours of stroke symptom onset. 


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What are the inclusion and exclusion criteria in PRECIOUS?

In order to be eligible to participate in this study, a subject must meet all of the following 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 Scale62 (NIHSS) ≥ 6, indicating moderately severe to severe stroke;
  3. Age 66 years or older;
  4. The possibility to start treatment within 12 hours of symptom onset;
  5. Written informed consent.

A subject who meets any of the following criteria will be excluded from participation in this study:


  1. Active infection requiring antibiotic treatment, as judged by the treating physician;
  2. Clinical indication for one or more of the drugs tested in this patient;
  3. Pre-stroke score on the mRS ≥;
  4. Death appearing imminent at the time of assessment.

In addition, patients will be excluded from participation in the trial treatment strata for any of the following reasons, which are standard for use of the interventions in clinical routine:

For the metoclopramide stratum:

  1. Hypersensitivity to metoclopramide or to any of the excipients;
  2. Gastrointestinal haemorrhage, mechanical obstruction or gastro-intestinal perforation for which the stimulation of gastrointestinal motility constitutes a risk;
  3. Confirmed or suspected pheochromocytoma;
  4. History of neuroleptic or metoclopramide-induced tardive dyskinesia;
  5. Epilepsy;
  6. Parkinson's disease;
  7. Use of levodopa or dopaminergic agonists;
  8. Known history of methaemoglobinaemia with metoclopramide or of NADH cytochrome-b5 deficiency.

For the ceftriaxone stratum:

  1. Known hypersensitivity to beta-lactam antibiotic.

For the paracetamol stratum:

  1. Known hypersensitivity to paracetamol or any of the excipients;
  2. Known severe hepatic insufficiency;
  3. Chronic alcoholism.


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What are the primary and secondary outcome measures in PRECIOUS?

The primary outcome measure is the modified Rankin Scale (mRS) score at 90 days (± 14 days).

The secondary outcomes assessed at 7 days (± 1 day) or at discharge, if earlier, are:

  • Infections in the first 7 days (± 1 day; frequency, type, and C. difficile infections). 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 complete hospital admission for stroke, converted to units of defined daily doses according to the classification of the WHO Anatomical Therapeutic Chemical Classification System with Defined Daily Doses Index (http://www.whocc.no/);
  • SAEs in the first 7 days.
  • In a subgroup of patients: presence of Extended-Spectrum Beta-Lactamase (ESBL)-producing bacteria as detected by PCR in a rectal swab at day 7 (± 1 day, or at discharge, if earlier).

The secondary outcomes assessed at 90 days (± 14 days) are:

  • 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: the number of nights among the first 90 since stroke onset that are spent in the patient’s own home or a relative’s home. Resource use will be censored at 90 days. Where final follow-up occurs earlier, the last known placement will be extrapolated to 90 days;
  • Patient location over first 90 days (± 14 days): hospital; rehabilitation service; chronic nursing facility; home.


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What is a 2*2*2 factorial design?

As displayed in the figure below, patients will be allocated to one of eight treatment groups. Patient can be allocated to any possible combination of standard of care, paracetamol, metoclopramide and ceftriaxone. However, the trial should not be considered as a randomized clinical trial with 8 treatment arms, but as 3 randomized clinical trials performed within 1 trial. This means that patients in the trial will be analyzed as having ceftriaxone vs. no ceftriaxone, paracetamol vs. no paracetamol and metoclopramide vs. no metoclopramide.
Investigators will have the opportunity to censor a single randomisation stratum in a specific patient before randomisation, for example in case of an allergy to one of the interventions.
Allocation will be based on proportional minimisation through a web-based allocation service, which means that treatment allocation will be stratified by country and will include the following minimisation factors for balance in baseline characteristics: age (66 – 75 years vs. > 75 years); sex (male vs. female); stroke type (ischaemic stroke vs. intracerebral haemorrhage); stroke severity (NIHSS 6 – 12 vs. > 12); and diabetes mellitus (yes vs. no).


Treatman Groups


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How are Adverse Events (AEs) and Serious Adverse Events (SAEs) reported in PRECIOUS?

All AEs grade 3 to 5 will be documented in the site´s source documents and subject eCRF (whether or not related to the IMP). AEs grade 1 or 2 do not have to be documented in the eCRF or reported to the Study Safety Desk.  The recording and reporting period for all AEs (including SAEs) will begin after randomisation and end on day 7, except for SARs and SUSARs. Any AE that occurs for the first time after day 7 is highly unlikely to be related to any of the IMPs. However, any SAE occurring between day 7 and the end of follow-up on day 90 (± 14 days) for which a causal relationship between the IMP and the SAE is considered at least a reasonable possibility (i.e., SARs and SUSARs) should be reported as  SAE. All SAEs, except for expected SAEs (see below), occurring between randomisation and day 7 have to be reported within 24 hours of Investigator’s first awareness about the event, to the Study Safety Desk:

CTC North Safety Desk

Expected SAEs are events that are known to occur in the condition under study or with the IMPs used in the trial as defined in their SmPCs. Expected SAEs are defined in the protocol (Appendices 7 and 8). Expected SAEs as well as study endpoints are excluded from expedited reporting but should be documented in the eCRF and reported to the Safety Desk within 7 days of the Investigator’s first awareness about the event.


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What is the aim of obtaining rectal swabs is the resistance sub-study performed in PRECIOUS?

To detect selection of bacteria with 3rd generation cephalosporin resistance caused by increased antibiotic pressure, a nested case-control substudy will be performed in 1000 patients in 30 centres in different participating countries. The presence of ESBL-producing bacteria will be assessed with PCR. With this purpose two rectal swabs will be collected in each patient, after specific informed consent, on admission and at day 7 (± 1 day, or at discharge, if earlier) and sent to the central laboratory at the AMC in Amsterdam, the Netherlands. The sample size is based on resistance rates in E. coli, because of the high carriage rate of Escherichia coli in the population in general. Nevertheless, resistance in other Enterobacteriaceae (such as Klebsiella pneumoniae) and enterococci will also be investigated.


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