E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HSV encephalitis |
encéphalites à HSV |
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E.1.1.1 | Medical condition in easily understood language |
herpes virus encephalitis |
encéphalites à virus herpétique |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10014590 |
E.1.2 | Term | Encephalitis herpes |
E.1.2 | System Organ Class | 100000013665 |
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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 |
Estimate the interest of corticoids for the improvement of the neuropsychological forecast in 6 and 18 months |
Evaluer l’intérêt des corticostéroïdes pour l’amélioration du pronostic neuropsychologique à 6 et 18 mois chez des patients traités pour encéphalites à HSV |
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E.2.2 | Secondary objectives of the trial |
• Neuropsychological and Cognitive outcome measures [at 30 days/discharge, 6 and 18 months] • Clinical Outcome • Functional Outcomes [at 30 days/discharge, 6 months and 18 months] • Imaging Outcomes [Baseline, 2 weeks, 6 months and 18 months] • Biomarker outcomes [Baseline, 4 days, 2 weeks, 6 months months] • Safety Outcomes [2 weeks] • Health Status and Quality of Life [6 months and 18 months] |
• Evolution neuropsychologique et cognitive à 30 jours, 6 et 18 mois • Evolution clinique • Evolution fonctionnelle à 30 jours, 6 et 18 mois • Imagerie à l’inclusion, 2 semaines, 6 et 18 mois • Evaluation des biomarqueurs à l’inclusion, 4 jours 2 semaines, 6 et 18 mois • Evaluation de la sécurité à 2 semaines • Evaluation de la qualité de vie à 6 et 18 mois
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Suspected encephalitis criteria: Acute or subacute (up to 4 weeks) alteration in consciousness, cognition, personality or behaviour* persisting for > 24 hours. 2. Laboratory confirmed HSV by positive PCR on CSF sample. 3. Receiving intravenous aciclovir dosed at 10mg/kg TDS or at a reduced dose in renal impairment 4. Age ≥ 18 years 5. Written informed consent has been given by the patient or their legal representative
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1. Critères d’encéphalite: Altération aiguë ou subaiguë (jusqu’à 4 semaines) de la conscience, de la connaissance, de la personnalité ou trouble du comportement persistant plus de 24 heures. 2. Encéphalite à HSV confirmée par une PCR positive dans le LCS. 3. Traité par aciclovir intraveineux, 10mg/kg X3 par jour ou à une posologie adaptée en cas d’insuffisance rénale 4. Age ≥ 18 ans 5. Consentement éclairé signé par le patient ou son représentant légal
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E.4 | Principal exclusion criteria |
1. Currently receiving oral or injectable corticosteroid therapy; including treatment with oral or injectable corticosteroids in the last 30 days. 2. History of hypersensitivity to corticosteroids 3. Immunosuppression secondary to: - Known HIV infection & CD4 count under 200cell/mm3 - Biologic therapy or other immunosuppressive agents [azathioprine, methotrexate, ciclosporin] - Solid organ transplant on immunosuppression - Bone marrow transplant - Currently undergoing a course of chemotherapy or radiotherapy - Known immunodeficiency syndrome [other than HIV] - Known haematological malignancy 4. Pre-existing indwelling ventricular devices 5. Peptic ulcer disease in the last 6 months: defined as a peptic ulcer seen at previous endoscopy or an upper gastrointestinal bleed causing ≥ 2 unit haemoglobin drop 6. Currently on an antiretroviral regime containing rilpivirine 7. Subject under administrative or judicial control, person who are protected under the act. 8. Pregnant women, breastfeeding and parturient
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1. Traitement en cours par corticoïdes par voie orale ou injectable ou administré dans les 30 jours précédents 2. Antécédents d’hypersensibilité aux corticoïdes 3. Immunosuppression secondaire à: a. Infection connue par le VIH et taux de CD4 < 200 cellules/mm3 b. Biothérapie ou autres traitements immunosuppresseurs [azathioprine, methotrexate, ciclosporine] c. Transplantation d’organe solide ou immunosuppression d. Greffe de moelle e. Chimiothérapie ou radiothérapie en cours f. Syndrome d’immunodépression [autre que VIH] g. Hémopathie connue 4. Dérivation ventriculaire pré-éxistante 5. Ulcère peptique gastrique dans les 6 mois précédents: objectivé au cours d’une endoscopie précédente ou une hémorragie digestive haute responsable d’une perte de 2 points d’hémoglobine 6. Traitement antirétroviral contenant de la rilpivirine, en cours 7. Patients protégés par les articles L1121-6 et L1121-7 du code de la santé publique
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E.5 End points |
E.5.1 | Primary end point(s) |
Verbal memory score, as determined by the Wechsler Memory Scale (WMS-IV) Auditory Memory Index |
Wechsler Memory Scale (WMS-IV) Auditory Memory Index |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Neuropsychological outcome measures [6 months and 18 months] - Visual, immediate and delayed memory (WMS-IV), Processing speed and working memory(WAIS-IV), Language (NAB) & Higher executive function (Trail Making Tests Past A and B) - Anxiety and Depression (BDI & BAI) - Premorbid cognitive ability (TOPF) - Subjective cognitive complaints (Perceived Deficits Questionnaire)
Cognitive Outcome Measures [at 30 days/discharge, 6 and 18 months] - Addenbrooke’s Cognitive Assessment revised (ACE-III)
Clinical Outcome - Incidence of epilepsy - Time to hospital discharge - Requirement of HDU/ITU admission - Time to cessation of ventilator support [if any] - Time to recovery of GCS - Survival
Functional Outcomes [at 30 days/discharge, 6 months and 18 months] - Modified Rankin Score, Barthel Index, Liverpool Outcome Score and Glasgow Outcome Score
Imaging Outcomes [Baseline, 2 weeks, 6 months and 18 months] - Temporal lobe volume (as % of intra-cranial volume). - Whole brain volume (as % of intra-cranial volume). - Volume of affected region as seen on FLAIR image (as % of intra-cranial volume). - Volume of affected region as seen on diffusion-weighted image (as % of intra-cranial volume).
Biomarker outcomes [Baseline, 4 days, 2 weeks, 6 months months] - Transcriptomic and proteomic profiling on blood at baseline, 4 days, 2 weeks and 6 months & CSF at baseline and 2 weeks - Anti NMDA receptor antibody testing at 4 days and 6 months
Safety Outcomes [2 weeks] - Proportion of patients with detectable HSV in CSF
Health Status and Quality of Life [at 6 and 18 months] - Measured by the EuroQOL-5D-5L and SF-36
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Evaluation Neuropsychologique et cognitive à 30 jours, 6 et 18 mois 1. Wechsler Memory Scale version IV (WMS-IV); 2. Wechsler Adult Intelligence Scale version IV (WAIS-IV); 3. Language Module in the Neuropsychology Assessment Battery (NAB); 4. Trail Making Test Parts A and B; 5. Test of Premorbid Function (TOPF); 6. Tests auto-administrés: Beck Depression Inventory et Beck Anxiety Inventory; 7. Questionnaire sur la perception d’un déficit 8. Addenbrooke’s Cognitive Assessment (ACE-III)
Evaluation fonctionnelle à 30 jours, 6 et 18 mois Modified Rankin Score, Barthel Index, Liverpool Outcome Score and Glasgow Outcome Score
Evaluation Clinique - Incidence d’épilepsie - Durée d’hospitalisation - Requirement of HDU/ITU admission - durée de la ventilation mécanique (si nécessaire) - délais de retour à un score Glasgow normal - survie
Imagerie à l’inclusion, 2 semaines, 6 et 18 mois - Mesure du volume du lobe temporal - Mesure du volume cérébral global - Mesure du Volume de la région atteinte
Evolution des biomarqueurs - profil transcriptomique et protéomique sur le LCR à l’inclusion, et J+ 2 semaines; sur le sang à l’inclusion, J+4 jours, 2 semaines et 6 mois - Anticorps Anti récepteur-NMDA évalués à J+4 et J+ 6 mois
Evaluation de la sécurité - Proportion de patients pour laquelle un HSV positif est détecté au bout de 2 semaines dans le LCR
Evaluation de la qualité de vie à 6 et 18 mois Mesurée via les questionnaires EuroQOL-5D-5L et SF-36
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline, J+4 days 2 weeks 30 days/discharge 6 months 18 months |
a l'inclusion, J+4 jours 2 semaines 30 jours ou sortie de l’hôpital 6 mois 18 mois |
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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 | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
L'évaluation de l'objectif principal sera faite par un évaluateur en aveugle |
The primary outcome will be observer blinded. |
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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 |
pas de comparateur, il n'y a pas de dexamethasone dans le 2nd groupe |
no comparator, the second arm doesn't received dexamethasone |
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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 | 9 |
E.8.5 | The trial involves multiple Member States | No |
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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LVLS |
la fin de l'étude correspond à la dernière visite du dernier patient inclus. |
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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 | 6 |
E.8.9.1 | In the Member State concerned days | 0 |