| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hereditary Angioedema (HAE) |
| Angioedema ereditario |
|
| E.1.1.1 | Medical condition in easily understood language |
| Disease that causes episodes of severe swelling in the body |
| Malattia che provoca episodi di grave gonfiore nel corpo |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10080953 |
| E.1.2 | Term | Hereditary angioedema with normal C1 esterase inhibitor |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| 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 |
| To describe the pharmacokinetic (PK) parameters of berotralstat administered orally to pediatric subjects with HAE aged 2 to < 12 years old and weighing = 12 kg. |
| Descrivere i parametri farmacocinetici (PK) di berotralstat somministrato per via orale a soggetti pediatrici con AEE di età compresa tra 2 e <12 anni e peso =12 kg. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the safety and tolerability of berotralstat administered orally to pediatric subjects with HAE aged 2 to < 12 years old and weighing = 12 kg.
- To describe the effectiveness of berotralstat in pediatric subjects with HAE aged 2 to < 12 years old and weighing = 12 kg. |
- Valutare la sicurezza e la tollerabilità di berotralstat somministrato per via orale a soggetti pediatrici con AEE di età compresa tra 2 e <12 anni e peso =12 kg.
- Descrivere l’efficacia di berotralstat in soggetti pediatrici con AEE di età compresa tra 2 e <12 anni e peso =12 kg. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and non-pregnant, non-lactating females 2 to < 12 years of age and weighing = 12 kg.
2. Parent/caregiver willing and able to provide written, informed consent (with assent from the child where appropriate).
3. Subjects with a clinical diagnosis of HAE. A clinical diagnosis of HAE is defined as:
• Laboratory documentation of historical C1-INH deficiency results (<50% of normal levels) and a complement 4 (C4) level below the lower limit of the normal (LLN) reference range.
OR
• Historical or new laboratory documentation of historical C1-INH functional level below the assay lower limit of normal
OR
• For subjects with C1-INH function = 50% but less than the assay LLN, a SERPING-1 gene mutation known or likely to be associated with HAE Type I or II, as assessed during the screening period OR a repeat C1-INH functional level < 50% will be considered acceptable for enrollment.
OR
• Historical or new laboratory documentation of a SERPING-1 mutation known or likely to be associated with HAE
OR
• For subjects who currently use plasma-derived or recombinant C1-INH-based therapies, a confirmed family history of C1-INH deficiency.
4. For subjects who are not currently receiving prophylaxis for HAE, documented history of = 2 HAE attacks in the 6 months prior to the enrollment visit.
5. Access to and ability to use one or more acute medications approved by the relevant competent authority for the treatment of acute attacks of HAE.
6. In the opinion of the investigator, the subject would benefit from long-term oral prophylaxis.
7. Females who had started their menses and males must be either:
- Sexually abstinent (Section 9.2.2.2 of the protocol ); OR
- If sexually active , or become sexually active during the study, must agree to the use of effective contraception (Section 9.2.2.2 of the protocol ) |
1. Età compresa tra 2 e <12 anni e peso =12 kg.
2. Genitore/Caregiver disposto a, e in grado di fornire consenso informato scritto (con l’assenso del bambino, se del caso).
3. Diagnosi clinica di AEE. Una diagnosi clinica di AEE è definita come:
Risultati documentati che indichino un deficit di C1-inibitore (C1-INH) immunogenico e/o
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funzionale (<50% dei livelli normali) e livello di complemento 4 (C4) al di sotto del limite inferiore dell’intervallo di riferimento normale (LLN) OPPURE
• Documentazione di laboratorio di livello funzionale anamnestico di C1-INH al di sotto del limite inferiore della norma previsto dal test
OPPURE
• Documentazione di laboratorio di mutazione di SERPING-1 nota per essere associata o probabilmente associata all’AEE
OPPURE
• Per i soggetti in corso di trattamento con terapie a base di C1-INH derivato dal plasma o ricombinante, anamnesi familiare confermata di deficit di C1-INH.
4. Per i soggetti non attualmente in profilassi per l’AEE, anamnesi documentata di =2 attacchi di AEE nei 6 mesi precedenti la visita di arruolamento.
5. Accesso a, e possibilità di utilizzare uno o più farmaci acuti approvati dall’autorità competente pertinente per il trattamento degli attacchi acuti di AEE.
6. A giudizio dello sperimentatore, possibile beneficio per il soggetto dalla profilassi orale a lungo termine.
7. In caso di soggetto sessualmente attivo o che diventa sessualmente attivo durante lo studio, consenso all’uso di un metodo contraccettivo efficace. |
|
| E.4 | Principal exclusion criteria |
1. Concurrent diagnosis of any other type of recurrent angioedema.
2. Any clinically significant history of angina, myocardial infarction, syncope, clinically significant cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, myocarditis, pericarditis, congenital heart defects, or any other clinically significant cardiovascular abnormality such as poorly controlled hypertension.
3. Known family history of sudden cardiac death. Family history of sudden death from HAE is not exclusionary.
4. History of or current implanted defibrillator or pacemaker.
5. Moderate to severe hepatic impairment (Child-Pugh B or C).
6. A calculated creatinine clearance using the Modified Schwartz formula of = 30 mL/min/1.73 m2 or aspartate aminotransferase or alanine aminotransferase value = 3 × the upper limit of the age-appropriate normal reference range value.
7. History of severe hypersensitivity to multiple medicinal products or severe hypersensitivity/anaphylaxis with unclear etiology.
8. Current participation in any other investigational drug study or received another investigational drug within 30 days of enrollment; not willing to refrain from participation in another clinical study after enrollment and for the duration of the study. [Note: drugs/vaccines approved under FDA emergency use authorization (or country-specific analogous regulations) are not considered excluded or prohibited under this criterion.]
9. An immediate family relationship to either sponsor employees, the investigator, or employees of the study site named on the delegation log.
10. Any clinically significant medical condition or medical history (including altered mental status) that, in the opinion of the investigator or sponsor, would interfere with the subject’s safety or ability to participate in the study. Examples include but are not limited to active malignancy under treatment, uncontrolled cardiovascular disease, organ dysfunction requiring supportive care.
11. Clinically significant abnormal ECG including but not limited to, a corrected QT interval calculated using Fridericia’s correction (QTcF = QT/RR0.33) > 450 msec, or ventricular and/or atrial premature contractions that are more frequent than occasional, and/or as couplets or higher in grouping.
12. Any result at screening that, in the opinion of the investigator, is clinically significant and relevant for this study. |
1. Diagnosi concomitante di qualsiasi altro tipo di angioedema ricorrente.
2. Qualsiasi anamnesi clinicamente significativa di angina, infarto del miocardio, sincope, aritmie cardiache clinicamente significative, ipertrofia ventricolare sinistra, cardiomiopatia, miocardite, pericardite, difetti cardiaci congeniti o qualunque altra anomalia cardiovascolare clinicamente significativa come ad esempio ipertensione scarsamente controllata.
3. Anamnesi familiare nota di decesso cardiaco improvviso. Un’anamnesi familiare di decesso improvviso per AEE non rappresenta un motivo di esclusione.
4. Impianto attuale o anamnestico di defibrillatore o pacemaker.
5. Insufficienza epatica da moderata a grave (Child-Pugh B o C).
6. Clearance della creatinina calcolata con la formula di Schwartz modificata =30 ml/min/1,73 m2 o valore di aspartato aminotransferasi o alanina aminotransferasi =3 × il limite superiore dell’intervallo di riferimento normale appropriato per l’età.
7. Anamnesi di grave ipersensibilità a più medicinali o grave ipersensibilità/anafilassi ad eziologia incerta.
8. Attuale partecipazione a qualsiasi altro studio su un farmaco sperimentale o trattamento con un altro farmaco sperimentale entro 30 giorni dall’arruolamento; rifiuto di astenersi dalla partecipazione a un altro studio clinico dopo l’arruolamento e per la durata dello studio. [Nota: questo criterio non esclude né vieta i farmaci/vaccini approvati ai sensi dell’autorizzazione all’uso di emergenza della Food and Drug Administration (FDA) (Ente preposto alla tutela di alimenti e medicinali) (o di analoghe normative nazionali specifiche).]
9. Rapporto di parentela stretto con dipendenti dello sponsor, con lo sperimentatore o con
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dipendenti del centro sperimentale indicati nel registro delle deleghe.
10. Qualsiasi condizione medica o anamnesi clinicamente significativa (comprese eventuali alterazioni dello stato mentale) che, a giudizio dello sperimentatore o dello sponsor, potrebbe interferire con la sicurezza del soggetto o con la sua capacità di partecipare allo studio; per esempio, in modo non limitativo: neoplasia attiva in corso di trattamento, malattia cardiovascolare non controllata, disfunzione d’organo con necessità di terapia di supporto.
11. Anomalie clinicamente significative dell’ECG, tra cui, in modo non limitativo, intervallo QT corretto calcolato utilizzando la correzione di Fridericia (QTcF=QT/RR0,33) >450 msec, oppure contrazioni ventricolari e/o atriali premature che si manifestano con frequenza non occasionale e/o si presentano in coppie o a gruppi di più di due.
12. Qualsiasi risultato durante lo screening che, a giudizio dello sperimentatore, sia clinicamente significativo e rilevante per questo studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PK : The primary endpoint is the characterization of the PK profile of berotralstat in subjects aged 2 to < 12 years. |
| PK: l’endpoint primario è la caratterizzazione del profilo PK di berotralstat in soggetti di età compresa tra 2 e <12 anni. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint will be evaluated at week 2, part 1 and at week 48, part 2 of the study for each cohort of patients. |
| L'endpoint primario sarà valutato alla settimana 2, parte 1 e alla settimana 48, parte 2 dello studio per ciascuna coorte di pazienti. |
|
| E.5.2 | Secondary end point(s) |
Safety : The frequency and severity of adverse events (AEs) and serious adverse events (SAEs), laboratory analyses (clinical chemistry, hematology, coagulation), height, weight, vital signs, electrocardiograms (ECGs), and physical examination findings
Effectiveness: The frequency of attacks, duration of symptoms, anatomical location of attack, on-demand treatment, number of days with angioedema symptoms, assessment of attack severity, discontinuations due to lack of efficacy, and number of hospitalizations and clinic visits from Week 1 through Weeks 12 and 48 |
- Sicurezza: frequenza e gravità degli eventi avversi (EA) e degli eventi avversi seri (SAE),
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analisi di laboratorio (chimica clinica, ematologia, coagulazione), altezza, peso, segni vitali, elettrocardiogrammi (ECG) e risultati degli esami obiettivi.
- Efficacia: frequenza degli attacchi, durata dei sintomi, sede anatomica dell’attacco, trattamento al bisogno, numero di giorni con sintomi di angioedema, valutazione della gravità dell’attacco, interruzioni dovute a mancanza di efficacia e numero di ricoveri e visite in clinica dalla Settimana 1 alle Settimane 12 e 48. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety endpoints will be assessed at the end of each Part (ie, Weeks 12, 48, and 144/end of study [EOS]).
The other secondary endpoint of effectiveness will be measured by assessing the frequency of attacks, duration of symptoms, anatomical location, on-demand treatment required, number of days with angioedema symptoms, assessment of attack severity, discontinuations due to lack of efficacy, and number of hospitalizations and clinic visits from Week 1 through Weeks 12 and 48.
|
| Questionario adeguato all’età relativo alla palatabilità/accettabilità di berotralstat granuli orali come valutata dal centro dopo la prima dose. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, effectiveness |
| Tollerabilità, efficacia |
|
| 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 | 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) | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 |
| Israel |
| Austria |
| France |
| Poland |
| Romania |
| Spain |
| Germany |
| Italy |
| Hungary |
| North Macedonia |
| United Kingdom |
|
| 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
|
| The end of study will be defined as when the last subject completes the last protocol-scheduled visit or sponsor-defined last visit should study be terminated early. |
| La fine dello studio sarà definita dall'ultimo soggetto che completa l'ultima visita programmata dal protocollo o l'ultima visita definita dallo sponsor se lo studio deve essere interrotto anticipatamente. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 20 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 35 |
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