PREvention of Complications to Improve Outcome in elderly patients with acute Stroke.

• Register: EUCTR
• Last refreshed on: 19 November 2018
• Main ID: EUCTR2015-003179-32-HU
• Date of registration: 07/07/2016
• Prospective Registration: Yes
• Primary sponsor: University Medical Center Utrecht
• Public title: PREvention of Complications to Improve Outcome in elderly patients with acute Stroke.
• Scientific title: PREvention of Complications to Improve Outcome in elderly patients with acute Stroke. A randomised, open, phase III, clinical trial with blinded outcome assessment. - PRECIOUS
• Date of first enrolment: 07/07/2016
• Target sample size: 3800
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003179-32
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: yes; Other trial design description: Blinded outcome assessment; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: yes; Other specify the comparator: standard care as defined by local protocols and national and/or international guidelines; Number of treatment arms in the trial: 8
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Estonia, Germany, Greece, Hungary, Italy, Netherlands, Norway, Poland, United Kingdom

Contacts

• Name: Clinical trial coordinator
• Affiliation: University Medical Center Utrecht

• Name: Clinical trial coordinator
• Affiliation: University Medical Center Utrecht

Key inclusion & exclusion criteria

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 3800

Exclusion criteria:
1. Active infection requiring antibiotic treatment, as judged by the treating physician;
2. Pre-stroke score on the mRS =4;
3. Death appearing imminent at the time of assessment.

In addition, patients will be excluded from participation in the trial treatment arms for any of the following reasons:
For the ceftriaxone arm:
1. Known hypersensitivity to beta-lactam antibiotics;
2. Clinical indication for antibiotic treatment; use of an antibiotic before screening is not an exclusion criterion.
For the paracetamol arm:
1. Known hypersensitivity to paracetamol or any of the excipients;
2. Known severe hepatic insufficiency;
3. Chronic alcoholism;
4. Clinical indication for the use of paracetamol; incidental use of paracetamol before screening is not an exclusion criterion.
For the metoclopramide arm:
1. Hypersensitivity to the 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;
9. Clinical indication for the use of metoclopramide; incidental use of metoclopramide before screening is not an exclusion criterion.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Stroke (ischaemic stroke or intracerebral hemorrhage)
MedDRA version: 20.0 Level: PT Classification code 10061256 Term: Ischaemic stroke System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 20.1 Level: LLT Classification code 10022754 Term: Intracerebral hemorrhage System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 20.0 Level: LLT Classification code 10042244 Term: Stroke System Organ Class: 10029205 - Nervous system disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Trade Name: Paracetamol
Product Name: Paracetamol
Pharmaceutical Form:
INN or Proposed INN: Paracetamol
CAS Number: 103-90-2
Current Sponsor code: AS3
Other descriptive name: PARACETAMOL

Trade Name: Ceftriaxone
Product Name: Ceftriaxone
Pharmaceutical Form: Powder and solvent for solution for infusion
INN or Proposed INN: CEFTRIAXONE
CAS Number: 73384-59-5

Trade Name: Metoclopramide
Product Name: Metoclopramide
Pharmaceutical Form:
INN or Proposed INN: METOCLOPRAMIDE
CAS Number: 364-62-5

Primary Outcome(s)

Primary end point(s): The primary outcome measure is the score on the modified Rankin Scale (mRS) at 90 days (± 14 days).

Timepoint(s) of evaluation of this end point: The primary outcome will be evaluated on day 90 (± 14 days).

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.

Main Objective: To assess whether prevention of aspiration, infections and fever with metoclopramide, ceftriaxone, paracetamol, or any combination of these, in the first four days after stroke onset improves functional outcomes at 90 days in elderly patients with acute stroke.

Secondary Outcome(s)

Secondary end point(s): 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 first 7 days.

Timepoint(s) of evaluation of this end point: As noted in E.5.2, the secondary outcomes will be on day 7(± 1 day) and day 90 (± 14 days).

Secondary ID(s)

ISRCTN82217627

2015-003179-32-NL

ToL54304

Source(s) of Monetary Support

European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 634809