E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Schizophrenia |
Schizofrenia |
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E.1.1.1 | Medical condition in easily understood language |
Schizophrenia |
Schizofrenia |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039626 |
E.1.2 | Term | Schizophrenia |
E.1.2 | System Organ Class | 10037175 - Psychiatric 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 |
Is mirtazapine as add-on therapy to antipsychotic treatment more effective than placebo for treatment of positive and negative symptoms of schizophrenia? |
La terapia con mirtazapina in aggiunta alla terapia antipsicotica già in atto è più efficace del placebo nel ridurre i sintomi positivi e negativi in pazienti con schizofrenia? |
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E.2.2 | Secondary objectives of the trial |
i) Is folic acid as add-on therapy to antipsychotic treatment more effective than placebo for treatment of positive and negative symptoms of schizophrenia? ii) Is mirtazapine as add-on therapy to antipsychotic treatment more effective than placebo for treatment of negative symptoms of schizophrenia measured on the negative symptoms scale of the PANSS? iii) Is folic acid as add-on therapy to antipsychotic treatment more effective than placebo for treatment of negative symptoms of schizophrenia measured on the negative symptoms scale of the PANSS? |
i) La terapia con acido folico in aggiunta alla terapia antipsicotica già in atto è più efficace del placebo nel ridurre i sintomi positivi e negativi della schizofrenia? ii) La terapia con mirtazapina in aggiunta alla terapia antipsicotica già in atto è più efficace del placebo nel ridurre i sintomi negativi della schizofrenia misurati alla scala per i sintomi negativi della PANSS? ii) La terapia con acido folico in aggiunta alla terapia antipsicotica già in atto è più efficace del placebo nel ridurre i sintomi negativi della schizofrenia misurati alla scala per i sintomi negativi della PANSS? |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. diagnosis of DSM-IV schizophrenia; 2. active psychotic symptoms (i.e. hallucinations, delusions, thought disorder); 3. minimum PANSS score 60; 4. inpatient or outpatient; 5. aged 16 to 70 years; 6. able and willing to consent to participate; 7. currently taking effective dose of antipsychotic; 8. clinically appropriate to change or augment treatment; 9. adjunctive mirtazapine appears reasonable and both investigator and patient are uncertain whether it will offer any benefit; 10. not pregnant, breast-feeding or planning a pregnancy; 11. adhering to antipsychotic treatment; 12. drug treatment stable. |
1. diagnosi di schizofrenia (DSM-IV); 2. presenza di sintomi psicotici (allucinazioni, deliri, disturbi del pensiero); 3. punteggio minimo alla PANSS di 60; 4. pazienti ambulatoriali e ricoverati; 5. età compresa tra i 16 e i 70 anni; 6. capacità di esprimere la volontà a partecipare allo studio; 7. assunzione di dosi adeguqte di antipsicotico; 8. è clinicamente indicato cambiare la terapia in atto e appare ragionevole poter aggiungere la mirtazapina; 9. non sussistono controindicazioni all'eventuale introduzione dei trattamenti in studio; 10. assenza di gravidanza, allattamento o previsione di gravidanza ; 11. adesione ai trattamenti; 12. trattamento farmacologico stabile. |
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E.4 | Principal exclusion criteria |
1. Meeting criteria for current manic episode, including schizoaffective disorder; 2. Current (i.e. within last 2 weeks) antidepressant treatment or considering treatment for depresison; 3. Contraindications to investigational medicinal products. If contraindication is to folic acid only, the patient can be randomised to the mirtazapine/placebo comparison only; 4. Currently taking clozapine. |
1. Criteri per un episodio maniacale (incluso il disturbo schizoaffettivo); 2. Attuale trattamento (entro 2 settimane)con antidepressivi o qualora si stia già considerando una terapia antidepressiva per la depressione; 3. Controindicazioni ai farmaci in studio. Se la controindicazione è solo per l'acido folico, il paziente può essere randomizzato solo al confronto mirtazapina/placebo; 4. Attuale trattamento con clozapina. assenza di trattamento con antidepressivo nelle ultime 2 settimane; |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome will be reduction in symptoms using the Positive and Negative Syndrome Scale, a 30-item rating scale widely used in assessment of medication effects in schizophrenia (Kay et al., 1987). Kay SR, Fiszbein A & Opler LA. Schizophrenia Bulletin 1987;13(2):261-76 |
The primary outcome will be reduction in symptoms using the Positive and Negative Syndrome Scale, a 30-item rating scale widely used in assessment of medication effects in schizophrenia (Kay et al., 1987). Kay SR, Fiszbein A & Opler LA. Schizophrenia Bulletin 1987;13(2):261-76 |
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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) |
i) Negative symptoms: there is no entirely satisfactory measure of negative symptoms but the PANSS negative subscale has the advantage of being both validated and commonly used (Lieberman et al. 2005; Stahl & Buckley 2007) and can be used to generate quality adjusted life years QALYs, a measure used in health economic evaluation (Rosenheck et al, 2006). ii) Depressive symptoms: the Calgary Depression Scale (Addington, Addington & Maticka-Tyndale 1993) will be used to quantify depressive symptoms. iii) Clinical Impression: the Clinical Global Impression Severity scale (CGI-S) (Guy 1976) will be used to measure overall severity of illness at each baseline and follow-up and the Clinical Global Impression - Improvement scale (CGI-I) will be used at each follow-up visit to rate change from baseline. iv) Akathisia: the Barnes Akathisia Scale (Barnes 1989) will be used to measure akathisia. v) Extra-pyramidal effects: Abbreviated Simpson–Angus scale (SAS) (Simpson & Angus 1970) will be used to measure extra pyramidal symptoms (EPS). vi) Tolerability: tolerability of mirtazapine and of folic acid will be measured by adherence to treatment. |
i) Negative symptoms: there is no entirely satisfactory measure of negative symptoms but the PANSS negative subscale has the advantage of being both validated and commonly used (Lieberman et al. 2005; Stahl & Buckley 2007) and can be used to generate quality adjusted life years QALYs, a measure used in health economic evaluation (Rosenheck et al, 2006). ii) Depressive symptoms: the Calgary Depression Scale (Addington, Addington & Maticka-Tyndale 1993) will be used to quantify depressive symptoms. iii) Clinical Impression: the Clinical Global Impression Severity scale (CGI-S) (Guy 1976) will be used to measure overall severity of illness at each baseline and follow-up and the Clinical Global Impression - Improvement scale (CGI-I) will be used at each follow-up visit to rate change from baseline. iv) Akathisia: the Barnes Akathisia Scale (Barnes 1989) will be used to measure akathisia. v) Extra-pyramidal effects: Abbreviated Simpson–Angus scale (SAS) (Simpson & Angus 1970) will be used to measure extra pyramidal symptoms (EPS). vi) Tolerability: tolerability of mirtazapine and of folic acid will be measured by adherence to treatment. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 15 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 25 |
E.8.9.2 | In all countries concerned by the trial days | 0 |