| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Down Syndrome |
| Sindrome di Down |
|
| E.1.1.1 | Medical condition in easily understood language |
| Down Syndrome |
| Sindrome di Down |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The aim of the study is to investigate the potential of 3 months of treatment with Bumetanide to rescue cognitive functions and associated psychopathological aspects in DS of Bumetanide treatment in children and adolescents with DS aged 10-16 years. The overreaching goal of our project is to test the ability of a treatment with Bumetanide to rescue cognitive functions and associated psychopathological aspects in children and adolescents with DS. As Bumetanide has been extensively used in the past in humans with little side effects, it is orally active, and it is very economical, we will test here the potentials of our therapeutic approach to be translated directly in a clinical trial on a cohort of DS patients. |
| Lo scopo di questo studio è esaminare il potenziale di una terapia di tre mesi con Bumetanide per migliorare le funzioni cognitive e gli aspetti psicopatologici associati alla sindrome di Down in pazienti di età compresa tra 10 e 16 anni. Lo scopo ulteriore del nostro progetto è verificare l’efficacia della terapia con Bumetanide per migliorare le funzioni cognitive e gli aspetti psicopatologici associati nella Sindrome di Down. Dato che il Bumetanide è stato ampiamente utilizzato in esseri umani provocando scarsi effetti collaterali, è attivo per via orale ed è molto economico, intendiamo con questo studio verificare il potenziale del nostro approccio terapeutico perché possa essere trasferito direttamente in una sperimentazione clinica con una coorte di pazienti con Sindrome di Down. |
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1)The presence of a free trisomy 21 documented by karyotyping
2)Adolescents from 10 to 16 years old (included)
3)Informed consent from each child and their parents.
|
Firma del consenso informato
Diagnosi genetica di sindrome di Down documentata da cariotipo;
Adolescenti tra i 10 ed i 16 anni
|
|
| E.4 | Principal exclusion criteria |
1) The presence of any neurosensory deficits, such as hypoacusis or serious visual impairments
2) The presence of epilepsy
3) The presence of disorders electrolytes
4) The presence of a hypersensibility known about sulpha drugs
5) The presence of contraindications relative to the treatment by bumetanide
6) Patients already treated by diuretics
7) Any of the following abnormal laboratory values at screening:
- Hemoglobin <10 g/dL
- Abnormal liver function defined as any 2 or more of the following: ≥3 × upper limit
of normal (ULN) aspartate aminotransferase (AST), ≥3 × ULN alanine
aminotransferase (ALT), ≥3 × ULN gamma-glutamyl transpeptidase (GGT),
≥3 × ULN alkaline phosphatase (ALP), or ≥2 × ULN total bilirubin
- Abnormal liver function defined as any increase of ≥5 × ULN AST or ALT
- Abnormal renal function defined as glomerular filtration rate
≤45 mL/min/1.73 m2 (calculated by the Scwartz equation)
8) A 12-lead ECG demonstrating QTc >450 msec at Screening
|
Presenza di deficit neurosensoriali
Presenza di epilessia
Presenza di disordini degli elettroliti
Presenza di ipersensibilità o controindicazioni note alla tipologia farmaceutica del Bumetanide
Pazienti già trattati con diuretici
Presenza di valori di laboratori anomali allo screening quali:
Emoglobina <10 g/dL
Presenza di alterazioni della funzionalità epatica definiti come 2 o più dei seguenti: ≥3 ULN aspartate aminotransferase (AST), ≥3 × ULN alanine aminotransferase (ALT), ≥3 × ULN gamma-glutamyl transpeptidase (GGT), ≥3 × ULN alkaline phosphatase (ALP), or ≥2 × ULN bilirubina totale
Presenza di alterazioni della funzionalità epatica definiti come ≥5 × ULN AST or ALT
Presenza di alterazioni della funzionalità epatica definiti come tasso di filtraggio glomerulare ≤45 mL/min/1.73 m2 (calcolato con l’equazione di Scwartz)
Presenza di un allungamento del QT all’elettrocardiogramma definite come QTc >450 msec
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary end-point will be a clinical improvement in the total score on visual-spatial episodic memory task (Promea). At month three we expect for the Bumetanide treatment group an improvement on the primary outcome measure comparable with the improvement in the normative sample, considering the test-retest reliability at three months (Vicari et al., 2007).
According to the test re-test reliability of the memory tasks for 3 months’ time interval in normative population (Promea - Vicari et al., 2007) and the correlation between the measures (r = 0.6), it has been considered clinically significant an increment of at least 5.1 of total scores, since it is comparable to typical developing controls improvement (Vicari et al., 2007).
|
| End point primario (ripetere se necessario): L’end-point primario sarà il miglioramento del punteggio totale sul task di memoria episodica visuo-spaziale (Promea). Al terzo mese prevediamo un miglioramento dell’outcome primario nel gruppo con Bumetanide, paragonabile con il miglioramento nel campione normativo, considerando l’affidabilità test-retest a tre mesi (Vicari et al., 2007).In base all’affidabilità test-retest dei task di memoria su un intervallo di tre mesi nella popolazione normativa (Promea - Vicari et al., 2007) e secondo la correlazione tra le misurazioni (r = 0.6), è stato considerato clinicamente significativo un incremento di almeno 5.1 del punteggio totale, dato che questo è paragonabile al miglioramento evolutivo nel gruppo di controllo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Secondary end-points will be clinical improvement after 3 months bumetanide treatment in the total scores of other episodic memory tasks (verbal and visual long term memory, associative memory) and in psychopathological measures as: standardized questionnaires and interviews as the Kiddie-Sads-Present and Lifetime Version (K-SADS-PL) (Kaufman et al., 2004), the Multidimensional Anxiety Scale For Children – MASC (March, 1997) and the The Conners 3rd Edition–Parent Parent Rating Scale–Revised: Long Version (CPRS-R:L;. Conners, 1997; Nobile, Alberti, & Zuddas, 2007). |
| Gli end-point secondari consisteranno nel miglioramento clinico dopo tre mesi di terapia con bumetanide e nei punteggi totali di altri task di memoria episodica (memoria verbale e visiva a lungo termine e memoria associativa), nonché nelle misure psicopatologiche, quali: questionari standardizzati e interviste, come la Kiddie-Sads-Present and Lifetime Version (K-SADS-PL) (Kaufman et al., 2004), la Multidimensional Anxiety Scale For Children – MASC (March, 1997) e la The Conners 3rd Edition–Parent Parent Rating Scale–Revised: Long Version (CPRS-R:L;. Conners, 1997; Nobile, Alberti, & Zuddas, 2007). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After 3 months |
| Dopo i 3 mesi |
|
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | No |
| 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
|
| LVLS |
| Ultima visita dell'ultimo paziente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 24 |
| E.8.9.1 | In the Member State concerned days | |
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