| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Neuromyelitis Optica Spectrum Disorder (NMOSD) |
| Disturbo dello spettro della neuromielite ottica (NMOSD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Neuromyelitis Optica Spectrum Disorder (NMOSD) |
| Disturbo dello spettro della neuromielite ottica (NMOSD) |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077879 |
| E.1.2 | Term | Neuromyelitis optica spectrum disorder relapse |
| E.1.2 | System Organ Class | 100000004852 |
|
| 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 |
| • Evaluate the efficacy of eculizumab in relapsing pediatric patients with Neuromyelitis Optica Spectrum Disorder (NMOSD) in the Primary Treatment Period. |
| • Valutare l’efficacia di eculizumab in pazienti pediatrici recidivanti affetti da disturbo dello spettro della neuromielite ottica (NMOSD) nel periodo di trattamento primario. |
|
| E.2.2 | Secondary objectives of the trial |
Primary Treatment Period:
• Evaluate the safety and tolerability of eculizumab treatment in
relapsing pediatric patients with NMOSD.
• Evaluate the efficacy of eculizumab by additional efficacy measures
including: disease-related disability, quality of life and change in
ophthalmologic examination findings.
• Describe the pharmacokinetics (PK) and pharmacodynamics (PD) of
eculizumab in relapsing pediatric patients with NMOSD.
Extension Treatment Period:
• Characterize long-term safety of eculizumab treatment in pediatric
patients with NMOSD.
• Characterize long-term efficacy of eculizumab treatment in pediatric
patients with NMOSD. |
• Valutare la sicurezza e la tollerabilità del trattamento con eculizumab in pazienti pediatrici recidivanti affetti da NMOSD.
• Valutare l’efficacia di eculizumab tramite misurazioni di efficacia aggiuntive, quali:
• Disabilità correlata alla malattia
• Qualità della vita
• Variazione nei risultati degli esami oftalmologici
• Descrivere la farmacocinetica (Pharmacokinetics, PK) e la farmacodinamica (Pharmacodynamics, PD) di eculizumab in pazienti pediatrici recidivanti affetti da NMOSD.
• Caratterizzare l’efficacia a lungo termine del trattamento con eculizumab in pazienti pediatrici affetti da NMOSD. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
assent/consent.
• Anti-AQP4 Ab-positive and diagnosis of NMOSD as defined by the 2015
IPND criteria
• Historical Relapse Rate of at least 2 relapses in the last 2 years, and
with at least 1 relapse in the year prior to Screening.
• Expanded Disability Status Scale score = 7
• Patients who enter the study receiving supportive immunosuppressive
therapies for the prevention of relapse, either in combination or monotherapy, must be on a stable dosing regimen of adequate duration
prior to Screening.
• Vaccinated against N meningitidis within 3 years prior to, or at the
time of initiating eculizumab. Patients who initiate study drug treatment
less than 2 weeks after receiving a meningococcal vaccine must receive
appropriate prophylactic antibiotics until 2 weeks after the vaccination.
• Documented vaccination against Hib and S pneumoniae infections 2
weeks prior to dosing as per local and country-specific immunization
guidelines for the appropriate age group.
• Willing and capable to give informed assent (if applicable, as
determined by the central Institutional Review Boards
(IRBs)/Independent Ethics Committees (IECs) and in accordance with
local requirements) and whose parent/legal guardian are willing and
able to give written informed consent, which includes compliance with
the requirements and restrictions listed in the informed consent form
(ICF) and in the protocol. |
- Pazienti maschi p femmine di età compresa tra 2 e <18 anni al tempo dell'assenso/consenso
- Anti-AQP4Ab positivo e diagnosi di NMOSD come definito dai criteri IPND 2015
- Storia di ricadute, almeno 2 negli ultimi 2 anni, e con almeno 1 ricaduta nell'anno precedente allo screening.
- Expanded Disability Status Scale score = 7
- I pazienti che entrano nello studio mentre ricevono terapie di supporto immunosoppressive per la prevenzione delle recidive, sia in combinazione che in monoterapia, devono essere in dosaggio stabile per un'adeguata durata prima dello screening.
- Vaccinati contro N meningitidis entro i 3 anni prima dello screening o nel momento in cui iniziano il trattament ocon Eculizumab. I pazienti che iniziano il trattamento meno di 2 settimane dopo aver ricevuto il vaccino menigococcico devono ricevere una profilassi antibiotica appropriata fino a 2 settimane dopo la vaccinazione.
- Vaccinazione documentata contro Hib e S pneumoniae 2 settimane prima del trattamento, secondo la legislazione locale in base all'età del gruppo di trattamento.
- Volontà e capacità di dare il proprio assenso informato e i cui genitori/tutori siano in grado di fornire il proprio consenso informato per iscritto. |
|
| E.4 | Principal exclusion criteria |
• Patients known to be human immunodeficiency virus (HIV) positive or
with congenital immunodeficiency.
• Unresolved meningococcal or other serious infection.
• Any unresolved acute or chronic systemic bacterial or other infection
which is clinically significant in the opinion of the Investigator and has
not been treated with appropriate antibiotics.
• Hypersensitivity to murine proteins or to one of the excipients of
eculizumab.
• Use of rituximab or other biologicals such as tocilizumab within 6
months prior to Screening.
• Use of mitoxantrone within 3 months prior to Screening.
• Use of intravenous immunoglobulin (IVIg) or plasma exchange (PE)
within 3 weeks prior to Screening.
• Use of immunomodulatory therapies for multiple sclerosis within 3
months prior to Screening. |
- Pazienti con diagnosi di Infezione da HIV o con immunodeficenza congenita
- Infezione meningococcica p di altro tipo seria e non risolta
- Qualsiasi infezione batterica acuta o cronica non risolta, che sia clinicamente significativa nell'opinione dello Sperimentatore e che non sia stata trattata con antibiotici appropriati.
- Ipersensibilità a proteine murine o a qualcun odegli eccipienti di Eculizumab.
- Uso di Rituximab o altri biologici come Tocilizumab entro i 6 mesi prima dello screening.
- Uso di mitoxantrone entro i 3 mesi prima dello screening.
- Uso di Rintravenous immunoglobulin (IVIg) o plasma exchange (PE) entro 3 settimane prima dello screening.
- Uso di terapie immunomodulatorie pre la sclerosi multipla entro 3 mesi prima dello screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Change from Baseline in the Annualized Relapse Rate (ARR).
• Time to First Relapse (TFR). |
• Variazione rispetto al basale del tasso di recidive annualizzato (Annualized Relapse Rate, ARR)
• Tempo alla prima recidiva (Time to First Relapse, TFR). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Treatment Period:
throughout the primary treatment period
and
52/53* Weeks
* For patients who start in weight cohort 10 to <20 kg, the one-year
evaluation will occur on Week 53, an odd-numbered week, because
maintenance dosing, which is administered every 2 weeks, begins on
Week 1. For all other cohorts the one-year evaluation will occur on Week
52, because maintenance dosing begins on an even-numbered week.
Hence, the end of the Primary Treatment Period is designated as Week
52/53 throughout the study protocol. |
Periodo di trattamento primario:
durante il periodo di trattamento primario e 52/53 settimane.
Per pazienti che partono nella coorte 10<20 kg, la valutazione ad 1 anno occorrerrà alla settimana 53, in una settimana dispari, poiché la dose di mantenimento, che viene somministrata ogni 2 settimane, comincia alla settimana 1. Per tutte le latre coorti, la valutazione ad 1 anno occorrerà alla settimana 52, perché la dose di mantenimento conincerà in una settimana pari.
Quindi, la fine del periodo di trattamento primario è indicata come la settimana 52/53 in accordo con il protocollo |
|
| E.5.2 | Secondary end point(s) |
Primary Treatment Period:
Safety:
• Incidence of treatment-emergent adverse events (TEAEs), serious
adverse events (SAEs), and adverse events leading to study drug
• Incidence of antidrug antibodies (ADA).
• Changes from Baseline in vital signs, electrocardiogram (ECG)
parameters, and clinical laboratory assessments.
• Change from Baseline in both weight and height.
Efficacy:
Disease-related disability:
• Change from Baseline in Expanded Disability Status Scale (EDSS) score
in patients =5 years of age.
• Change from Baseline in the Hauser Ambulatory Index (HAI) score.
Quality of life:
• Change from Baseline in Pediatric Quality of Life Inventory (PedsQL) in
patients =5 years of age.
• Change from Baseline in Pediatric Quality of Life Inventory Parent
Proxy (PedsQL Parent Proxy) in patients < 5 years of age.
Change in ophthalmologic examination findings:
• Change from Baseline in Visual Acuity (VA) as measured by the Snellen
or LEA symbols Eye Chart examination in all patients.
• Change from Baseline in Confrontational Visual Fields (VF) as
measured during ophthalmologic examination in all patients.
• Change from Baseline in color vision as measured during
ophthalmologic examination in all patients.
PK/PD:
• Changes in serum eculizumab concentration over time.
• Changes in serum free complement protein 5 (C5) concentrations and
in vitro hemolytic activity over time.
Extension Treatment Period:
The safety and efficacy endpoints of the Primary Treatment Period will
be evaluated during the Extension Treatment Period. |
• Incidenza degli eventi avversi che emergono in corso di trattamento (Treatment-Emergent Adverse Event, TEAE), eventi avversi gravi (Serious Adverse Event, SAE) ed eventi avversi che conducono a interrompere l’assunzione del farmaco sperimentale.
• Incidenza di anticorpi antifarmaco (Antidrug Antibody, ADA).
• Variazioni rispetto al basale dei parametri vitali, dei parametri dell’elettrocardiogramma (ECG) e delle valutazioni cliniche di laboratorio.
• Variazioni rispetto al basale sia di peso che di altezza
• Variazione rispetto al basale del punteggio della Scala della disabilità espansa (Expanded Disability Status Scale, EDSS) a 52/53 settimane in pazienti =5 anni di età.
• Variazione rispetto al basale del punteggio dell’indice di deambulazione di Hauser (Hauser Ambulation Index, HAI) a 52/53 settimane.
• Variazione rispetto al basale dell’inventario della qualità della vita pediatrica (Pediatric Quality of Life Inventory, PedsQL) a 52/53 settimane in pazienti =5 anni di età.
• Variazione rispetto al basale dell’inventario della qualità della vita pediatrica delegato al genitore (PedsQL Parent Proxy) a 52/53 settimane in pazienti <5 anni di età.
• Variazione rispetto al basale dell’acuità visiva (AV) misurata tramite l’esame delle tavole ottometriche di Snellen o dei simboli LEA a 52/53 settimane in tutti i pazienti.
• Variazione rispetto al basale dei campi di visione (Visual Field, VF) confrontazionali misurata nell’esame oftalmologico a 52/53 settimane in tutti i pazienti.
• Variazione rispetto al basale della visione a colori misurata nell’esame oftalmologico a 52/53 settimane in tutti i pazienti. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Primary Treatment Period:
throughout the primary treatment period
and
At 52/53* weeks
* For patients who start in weight cohort 10 to <20 kg, the one-year
evaluation will occur on Week 53, an odd-numbered week, because
maintenance dosing, which is administered every 2 weeks, begins on
Week 1. For all other cohorts the one-year evaluation will occur on Week
52, because maintenance dosing begins on an even-numbered week.
Hence, the end of the Primary Treatment Period is designated as Week
52/53 throughout the study protocol.
Extension Treatment Period:
104 weeks |
Periodo di trattamento primario:
durante il periodo di trattamento primario e 52/53 settimane.
Per pazienti che partono nella coorte 10<20 kg, la valutazione ad 1 anno occorrerrà alla settimana 53, in una settimana dispari, poiché la dose di mantenimento, che viene somministrata ogni 2 settimane, comincia alla settimana 1. Per tutte le latre coorti, la valutazione ad 1 anno occorrerà alla settimana 52, perché la dose di mantenimento conincerà in una settimana pari.
Quindi, la fine del periodo di trattamento primario è indicata come la settimana 52/53 in accordo con il protocollo.
Periodo di estensione del trattamento:
104 settimane |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability and immunogenicity |
| Tollerabilità e immunogenicità |
|
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Japan |
| Korea, Republic of |
| United States |
| Germany |
| Italy |
| Spain |
|
| 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
|
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 15 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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