E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute ischaemic stroke
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Ictus Ischemico Acuto |
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E.1.1.1 | Medical condition in easily understood language |
Acute stroke without bleeding in the brain |
Ictus acuto senza sanguinamento cerebrale |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061256 |
E.1.2 | Term | Ischaemic stroke |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether systemic cooling to a target body temperature between 34.0 and 35.0°C, started within 6 hours of symptom onset and maintained for 24 hours, improves functional outcome at 3 months in patients with acute ischaemic stroke. |
Determinare se il raffreddamento sistemico ad una temperatura target tra i 34.0 ed i 35.0°C, iniziato entro 6 ore dall'insorgenza dei sintomi e mantenuto per 24 ore, migliora l'outcome funzionale a 3 mesi nei pazienti con ictus ischemico acuto. |
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E.2.2 | Secondary objectives of the trial |
- To assess the effect of systemic cooling to a target body temperature between 34.0 and 35.0°C, started within 6 hours of symptom onset and maintained for 24 hours, in patients with acute ischaemic stroke on • mortality at 3 months. • neurological outcome at 3 months. • quality of life at 3 months. • cerebral infarct size at 48±24 hours.
- To determine the safety and tolerability of systemic cooling in patients with acute ischaemic stroke. |
- Valutare l’effetto del raffreddamento sistemico ad una temperatura target tra i 34.0 ed i 35.0°C, iniziato entro 6 ore dall'insorgenza dei sintomi e mantenuto per 24 ore, in pazienti con ictus ischemico acuto su • mortalità a 3 mesi. • outcome neurologico a 3 mesi. • Qualità della vita a 3 mesi. • dimensione dell'infarto cerebrale a 48 ± 24 ore.
- Determinare la sicurezza e la tollerabilità del raffreddamento sistemico in pazienti con ictus ischemico acuto.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The trial population consists of patients of both sexes, aged ≥18 years, with acute ischaemic stroke and a score on the NIHSS of 6 up to and including 18 at screening [Assessment 1, within 90 minutes before the start of the treatment phase TP].
- Written informed consent obtained from the patient or his/her legally acceptable representative or under such other arrangements as may be legally established in participating countries.
- Estimated body weight of 50kg up to and including 120kg.
- Possibility to start therapeutic hypothermia within 6 hours after onset of stroke.
- Possibility to start therapeutic hypothermia within 90 minutes after start of alteplase administration in patients receiving thrombolysis.
- Possibility to start therapeutic hypothermia within 90 minutes after admission to trial site in patients not receiving thrombolysis.
- mRS score ≤2 prior to onset of stroke.
- GCS motor response subscale score ≥5. |
La popolazione è costituita da pazienti di entrambi i sessi, di età ≥18 anni, con ictus ischemico acuto e un punteggio di NIHSS compreso tra 6 e 18 (estremi inclusi) allo screening [Assessment 1, entro 90 minuti prima dell’inizio della fase di trattamento TP].
- Consenso informato scritto ottenuto dal paziente o dal suo rappresentante legale o nell’ambito di altre disposizioni, stabilite legalmente nei paesi partecipanti.
- Peso corporeo stimato compreso tra 50kg e 120kg (estremi inclusi).
- Possibilità di iniziare l’ipotermia terapeutica entro 6 ore dall’insorgenza dell’ictus.
- Possibilità di iniziare l’ipotermia terapeutica entro 90 minuti dall’inizio della somministrazione di Alteplase in pazienti trattati con trombolisi presso il Centro Sperimentale.
- Possibilità di iniziare l’ipotermia terapeutica entro 90 minuti dopo l’accesso al Centro Sperimentale, in pazienti non trattati con trombolisi o in pazienti trattati con trombolisi in un diverso Centro.
- Punteggio mRS ≤2 prima dell’insorgenza dell’ictus.
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E.4 | Principal exclusion criteria |
1. Use of monoaminoxidase inhibitors in the 14 days prior to screening. 2. Current use of medication interacting with pethidine or buspirone. 3. Acute alcohol intoxication. 4. Opioid addiction. 5. Nursing mother or pregnant woman, as verified by a positive urine pregnancy test in females of childbearing potential. 6. Known hypersensitivity to the IMPs or any of their formulation ingredients. 7. Patient who is imprisoned or is lawfully kept in an institution. 8. Employee or direct relative of an employee of the CRO (if applicable), the department of the investigator, or the sponsor. 9. Participation in an interventional clinical trial within the last 4 weeks, or be under the exclusion period from another trial. 10. Prior participation in this trial. 11. Any acutely life-threatening conditions other than acute ischaemic stroke. 12. Rapidly resolving stroke symptoms. 13. Evidence from CT or MRI of intracranial haemorrhage or tumour or encephalitis or any diagnosis likely to cause the present symptoms other than acute ischaemic stroke. 14. Known convulsive disorder, acute closed angle glaucoma, myasthenia gravis. 15. SPO2 <94% (as measured by pulse oximetry) under nasal oxygen administration. 16. Other severe respiratory disorder. 17. Bradycardia (<40 bpm). 18. Severe cardiac failure, defined as NYHA classification ≥III. 19. Myocardial infarction or angina pectoris in the 3 months prior to screening. 20. Vasospastic disorders. 21. Haematological dyscrasia (e.g., sickle cell disease, cryoglobulinaemia). 22. Known platelet count <100,000/mm3. 23. Known INR >1.7. 24. Skin damage at the sites intended to be used for cooling. 25. Clinical diagnosis of sepsis. 26. Known severe hepatic impairment (serum ALAT and/or ASAT >3 times ULN). 27. Known renal impairment (serum creatinine >2mg/100ml). 28. Addison's disease. 29. Any other condition that may interfere with, or be aggravated by, therapeutic hypothermia. 30. Any condition that is thought to reduce the compliance to cooperate with the trial procedures |
1. Uso di inibitori delle monoaminossidasi nei 14 giorni prima dello screening. 2. Uso concomitante di farmaci che interagiscono con Petidina o Buspirone 3. Intossicazione acuta da alcool. 4. Dipendenza da oppiacei. 5. Madre in allattamento o donna in gravidanza, verificato con test di gravidanza delle urine positivo in donne in età fertile. 6. Ipersensitività agli IMPs o ad uno o più degli eccipienti. 7. Paziente in prigione on in detenzione obbligata. 8. Impiegato o parente diretto di un impiegato della CRO, del dipartimento dello sperimentatore o dello sponsor. 9. Partecipazione ad uno studio clinico interventistico nelle ultime 4 settimana o nel periodo di esclusione da un altro trial. 10. precedente partecipazione a questo trial. 11. Qualsiasi condizione che comporti rischio di vita a parte l'ictus ischemico acuto. 12. Sintomi di stroke in rapida risoluzione. 13. Evidenza da TC o RMN di emorragia intracerebrale o tumore o encefalite o di altra diagnosi che possa simulare uno stroke. 14. Disturbo convulsivo, glaucoma acuto ad angolo chiuso, miastenia grave. 15. SPO2 <94% (come da pulsossimetria) sotto somministrazione nasale di ossigeno. 16. Altri disturbi respiratori severi. 17. Bradicardia (<40 bpm). 18. Insufficienza cardiaca grave definita come NYHA classification ≥III. 19. Infaro miocardico o angina pectoris nei tre mesi antecedente lo screening. 20. Disturbi vasospastici. 21. Discrasia ematologica (e.g., anemia falciforme, crioglobulinemia). 22. Ipopiastrinemia <100,000/mm3. 23 INR >1.7. 24. Danno cutaneo nella sede prevista per il raffreddamento. 25. Sepsi clinica. 26. Insufficienza epatica severa (serum ALAT and/or ASAT >3 times ULN). 27. Insufficienza renale (serum creatinine >2mg/100ml). 28. Morbo di Addison. 29. Ogni altra condizione che possa interferire, o essere aggravata, dalla ipotermia terapeutica. 30. Ogni altra condizione ritenuta tale da ridurre la compliance a collaborare alle procedure dello studio .
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E.5 End points |
E.5.1 | Primary end point(s) |
1 Score on the mRS |
1 Punteggio di mRS |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At outcome assessment [A7, Day 91±14 days]. |
Alla valutazione dell'outcome [A7, Giorno 91±14 Giorni]. |
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E.5.2 | Secondary end point(s) |
1 Death or dependency, defined as a score on the mRS >2. 2 Death 3 Score on NIHSS. 4 Brain infarct size. 5 WHODAS 2.0 score 6 EQ-5D-5L score
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1 Decesso o dipendenza, definite come un punteggio di mRS >2 2 Decesso 3 Punteggio di NIHSS. 4 Dimensione dell’infarto cerebrale. 5 Punteggio di WHODAS 2.0. 6 Punteggio di EQ-5D-5L. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1Death or dependency, defined as a score on the mRS >2 at outcome assessment [A7, Day 91±14 days]. 2Death at outcome assessment [A7, Day 91±14 days] 3Score on NIHSS at outcome assessment [A7, Day 91±14 days]. 4Brain infarct size at imaging assessment [A4, Hour 48±24 hours]. 5WHODAS 2.0 score at outcome assessment [A7, Day 91±14 days]. 6EQ-5D-5L score at outcome assessment [A7, Day 91±14 days]. |
1Decesso o dipendenza, definite come un punteggio di mRS >2 alla valutazione dell’outcome [A7, Day 91±14 days]. 2Decesso alla valutazione dell’outcome [A7, Day 91±14 days]. 3Punteggio di NIHSS alla valutazione dell’outcome [A7, Day 91±14 days]. 4Dimensione dell’infarto cerebrale alla valutazione delle immagini [A4, Hour 48±24 hours]. 5Punteggio di WHODAS 2.0 alla valutazione dell’outcome [A7, Day 91±14 days]. 6Punteggio di EQ-5D-5L alla valutazione dell’outcome [A7, Day 91±14 days] |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Miglior trattamento medico. |
Best medical treatment. |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |