| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Edoxaban is being investigated for use in pediatric patients who may require anticoagulation therapy. |
Edoxaban verrà sperimentato per
l’uso nella popolazione pediatrica che necessita di terapie anticoagulanti |
|
| E.1.1.1 | Medical condition in easily understood language |
| A study of Edoxaban in children. |
| studio di Edoxaban nei bambini |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010495 |
| E.1.2 | Term | Congenital heart disease NOS |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057396 |
| E.1.2 | Term | Thrombophilia |
| E.1.2 | System Organ Class | 100000004851 |
|
| 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 |
| To characterize the PK of Edoxaban in pediatric patients following oral single-dose administration. |
| Caratterizzare la PK di edoxaban in pazienti pediatrici in seguito alla somministrazione orale di una dose singola |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the PD effects of edoxaban in pediatric patients following single-dose oral administration
- To evaluate the safety and tolerability of single-dose oral administration of edoxaban in pediatric patients
- To assess metabolite exposure (D21-2393, D21-3231, D21-1402, and D21-2135) in pediatric patients
- To evaluate the palatability (bitterness, sweetness, and overall taste or aroma) of the liquid oral suspension of edoxaban |
- Valutare gli effetti di PD di edoxaban in pazienti pediatrici in seguito alla somministrazione orale di una dose singola
- Valutare la sicurezza e la tollerabilità della somministrazione orale di
una dose singola di edoxaban in pazienti pediatrici
- Valutare l’esposizione al metabolita (D21-2393, D21-3231, D21-1402 e D21-2135) nei pazienti pediatrici
- Valutare la palatabilità (sapore amaro, dolce e il gusto o l’aroma
complessivamente) della sospensione orale liquida di edoxaban |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to provide written informed assents (patients, when applicable) and ICFs (signed by parent/legal guardian) prior to participating in the study
2. Male or female patients 0 to < 18 years of age on the day of dosing
3. Patients 2 to < 18 years of age must have a body mass index (BMI) between the 5th and 95th percentile based on the 2000 CDC Growth Charts7 (the maximum number of patients in each dose group that have a BMI between 85th and 95th percentile should not be more than 2 patients). Patients < 2 years of age must have a body weight between the 5th and 90th percentile based on the 2000 CDC Growth Charts7
4. Female patients who have had menarche must test negative for pregnancy at screening and check-in
5. Female patients who have had menarche and are sexually active must use an acceptable contraception method for at least 30 days prior to edoxaban dose
6. Patients/Legal guardian(s) must agree to food and drug restrictions during the study
7. Patients must agree to abstain from the use of nonsteroidal anti-inflammatory drugs (such as ibuprofen), and antiplatelet and anticoagulant agents (except for low-dose aspirin) from 24 hours prior to edoxaban dose until after the last PK sample is collected
8. Patients on low-dose aspirin treatment (1 to 5 mg/kg/day, maximum of 100 mg/day) with an interruption of aspirin 24 hours prior to edoxaban dose and resuming 24 hours after edoxaban dose are permitted to participate in the study per the Investigator’s judgment that this does not place the patients at risk
9. Patients must agree to abstain from CYP3A4 inhibitors/inducers and P-gp inhibitors/inducers for 14 days prior to the edoxaban dose to until after the last PK sample is collected (See Section 5.2)
10. Patients must agree to abstain from and/or legal guardians must agree not to give the patient cola, tea, coffee, chocolate, and other caffeinated drinks and food from 48 hours before dose administration through check-out (See Section 5.3 for a complete list)
11. Other than signs and symptoms characteristic to their disease state, patients are to be in good health as determined by the absence of clinically significant deviations from normal, with respect to medical and surgical history, physical examination, vital signs, and laboratory reports, as deemed by the Investigator and the Sponsor, prior to enrollment
12. Patients must agree to abstain from and/or legal guardians must agree not to give the patient St. John’s Wort and food/supplement and beverages containing grapefruit, grapefruit juice, and Seville oranges from 14 days before the first dose through the end of the study (See Section 5.3) |
- Pazienti che abbiano fornito il proprio consenso informato (quando applicabile) o i cui genitori/tutori legali abbiano dato il loro consenso
- Pazienti da 0 a < 18 anni di età di entrambi i sessi, che possono necessitare di terapia anticoagulante.
- Pazienti femmina che non siano incinte e che abbiano acconsentito all’uso di metodi contraccettivi per evitare una gravidanza durante il trattamento |
|
| E.4 | Principal exclusion criteria |
1. History (within the last 6 months) of abnormal coagulation tests during screening, as defined by local laboratory reference ranges, which are not explained by anticoagulation therapy
2. Stroke where anticoagulant therapy is contraindicated
3. Patients with stage 2 hypertension defined as blood pressure confirmed > 99th percentile + 5 mmHg
4. Patients with renal function less than 50% of normal for age and size as determined by the National Kidney Disease Education Program version of the Schwartz formula8
5. Actively bleeding or has a high risk of bleeding
6. Has a currently active gastrointestinal ulceration or a known history of peptic ulcer or gastrointestinal bleeding (including hematemesis, melena, or rectal bleeding including bleeding from hemorrhoids) within the previous 6 months
7. Has known diabetic retinopathy
8. Has thrombocytopenia at screening (< 20 × 109/L)
9. Has had other unrelated clinically significant illness within 4 weeks prior to Day 1, predose
10. Planned invasive procedures during or within 24 hours of study drug administration
11. Patient is receiving high-dose aspirin concurrently or within 2 weeks prior to dosing
12. Use of P-gp or CYP 3A4 inhibitors or inducers within 14 days prior to the edoxaban dose and expected to continue through the study duration
13. Patients with history of major bleeding and/or neurosurgery within 6 months of dosing
14. Patients with history of major trauma or surgery within the last month
15. Patients with known malabsorption disorders (e.g., cystic fibrosis or short bowel syndrome)
16. Hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk or alanine transaminase (ALT) > 5 times the upper limit of normal (ULN) or total bilirubin > 2 times the ULN with direct bilirubin > 20% of the total
17. Patient is currently enrolled in another investigational device or drug study, or is receiving other investigational agents. Patients must have completed the prior clinical study at least 30 days prior to dosing
18. Patients of childbearing potential (post-menarche) who are sexually active and are not using approved contraception; who are pregnant (as based on test results); or are breastfeeding
19. Females with history of abnormal menses, including history of menorrhagia (heavy menstrual bleeding), metrorrhagia, or polymenorrhea
20. Patient has known sensitivity to the investigational product (IP) or any of its excipients
21. Positive drug or alcohol screen (excluding cotinine) at screening for patients 12 years of age or older, for newborns and for patients who are being breastfed
22. Patients who have received a transfusion or any blood products within 30 days prior to the first dose
23. Any major bleeding during prior anticoagulant therapy
24. Patients with any condition, that as judged by the Investigator, would place the patient at increased risk of harm if he/she participated in the study |
- Pazienti che mostrino test della coagulazione anormali durante lo screening, non spiegabili con la terapia anticoagulante
- Pazienti soggetti a ictus dove la terapia anticoagulante è controindicata
- Pazienti con stadio 2 di ipertensione definita come pressione sanguigna confermata > 99th percentile + 5 mmHg
- Pazienti con funzionalità renale inferiore al 50% della norma per età e peso secondo quanto determinato dal National Kidney Disease Education Program versione della formula di Schwartz
- Pazienti con sanguinamenti in atto o ad alto rischio di sanguinamento
- Pazienti con un’ulcera gastrointestinale attiva o con una storia nota di ulcera peptica o sanguinamento gastrointestinale (compresi ematemesi, melena, o sanguinamento rettale compreso sanguinamento da emorroidi) nei 6 mesi precedenti
- Pazienti con storia clinica di retinopatia diabetica
- Pazienti con trombocitopenia allo screening (< 20 × 109/L)
- Pazienti che stanno assumendo o hanno assunto alte dosi di aspirina in concomitanza o entro 2 settimane prima del dosaggio
- Pazienti che fanno uso di inibitori o induttori della P-gp e del CYP3A4 entro 14 giorni prima della dose di edoxaban e dovrebbero proseguire la terapia per tutta la durata studio
- Pazienti con malattia epatica associata a coagulopatia che comporta un rischio emorragico clinicamente significativo o alanina transaminasi (ALT)> 5 volte il limite superiore del valore normale (ULN) o bilirubina totale> 2 volte il limite superiore normale con bilirubina diretta> 20% del totale |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- The PK endpoints will include PK parameters such as apparent systemic clearance (CL/F) and apparent volume of distribution (V/F). If data permit, derived PK parameters such as AUC and metabolite/parent ratios for AUCs will also be estimated.
|
Parametri di farmacocinetica, come
la clearance sistemica (CL/F) apparente, il volume di distribuzione (V/F) apparente e
l’area sotto la curva concentrazione-tempo (AUC) per edoxaban e metaboliti e rapporti
metabolita/farmaco progenitore per AUC. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PK:
- 0.25 to 1 hour postdose (1 sample)
- 1.5 to 3 hours postdose (1 sample)
- 3.5 to 6 hours postdose (1 sample)
- 6.5 to 8 hours postdose (1 sample)
- 8.5 to 14 hours postdose (1 sample)
- 24 to 36 hours postdose (1 sample)
- 48 to 54 hours postdose (1 sample)
For subsequent age cohorts, emerging PK concentration-time data from completing patients will be analyzed on an ongoing basis and used to refine and optimize the PK blood sampling scheme (i.e., both the number of samples and the sampling windows). |
Endpoint relativo alla PK:
- da 0,25 a 1 ora post- dose (1 campione)
- da 1,5 a 3 ore post- dose (1 campione)
- da 3,5 a 6 ore post- dose (1 campione)
- da 6,5 a 8 ore post- dose (1 campione)
- da 8,5 a 14 ore post- dose (1 campione)
- da 24 a 36 ore post- dose (1 campione)
- da 48 a 54 ore post-dose (1 campione)
For le coorti di età successive, dati sulla concentrazione-tempo saranno analizzati su base continuativa e utilizzati per perfezionare e ottimizzare lo
schema di campionamento del sangue PK |
|
| E.5.2 | Secondary end point(s) |
- The PD endpoints will include observed, change-from-baseline, and percent-change-from-baseline PT, aPTT, and anti-FXa.
- Safety assessments will include: AEs, physical examination findings, vital signs, standard hematology, clinical chemistry, coagulation, and urinalysis laboratory tests. Note, urinalysis will be performed with plastic bags with a sticky strip from neonates and infants with diapers.
- Palatability of the liquid formulation will be assessed using visual analog scale (VAS) scores. |
Endpoint relativo alla Farmacodinamica includerà i valori di PT, aPTT e anti-
FXa osservati, la loro variazione dal basale e la variazione percentuale dal
basale.
Endpoint relativo alla Sicurezza include la valutazione di eventi avversi, esiti
dell’esame obiettivo, segni vitali, valutazioni cliniche di laboratorio e
coagulazione e analisi delle urine.
Endpoint altri: palatabilità della formulazione liquida sarà valutata usando i
punteggi della scala analogica visiva (Visual Analog Scale, VAS). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Coagulation:
- Predose (1 sample)
- 0.25 to 1 hour postdose (1 sample)
- 1.5 to 3 hours postdose (1 sample)
- 3.5 to 6 hours postdose (1 sample)
- 6.5 to 8 hours postdose (1 sample)
- 24 to 36 hours postdose (1 sample)
All other secondary endpoints - throughout the study |
Coagulazione:
- Pre-dose (1 campione)
- Da 0.25 a 1 ora post dose (1 campione)
- da 1.5 a 3 ore post dose (1 campione)
- da 3.5 a 6 ore post dose (1 campione)
- da 6.5 a 8 ore post dose (1 campione)
- da 24 a 36 ore post dose (1 campione)
tutti gli altri endpoints saranno valutati nel corso dello studio |
|
| 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 | 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 |
| Metabolite exposure, palatability |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| 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 | No |
| 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 | 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.8.3 |
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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 | No |
| 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 |
| France |
| Italy |
| Spain |
| United Kingdom |
| United States |
| Jordan |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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