| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Opioid-induced constipation |
| Estreñimiento inducido por opioides. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment of constipation after taking opioid drugs |
| Tratamiento de estreñimiento causado por opioides |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Digestive System and Oral Physiological Phenomena [G10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071128 |
| E.1.2 | Term | Opioid induced constipation |
| E.1.2 | System Organ Class | 100000004856 |
|
| 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 pharmacokinetics (PK) of naloxegol after single oral dose and through population PK in paediatric patients with opioid induced constipation (OIC). |
| Definir la farmacocinética (FC) de naloxegol tras una dosis oral única y mediante la FC poblacional en pacientes pediátricos con estreñimiento inducido por opioides (EIO). |
|
| E.2.2 | Secondary objectives of the trial |
· To characterize the PK of naloxegol after multiple, once-daily, oral dosing in paediatric OIC patients who continue participation beyond Day 1. A minimum of 3 days of dosing is required for multiple-dose PK analysis.
· To evaluate the acceptability of the study medication in paediatric OIC patients through assessment of: 1) palatability of liquid formulation and, 2) the ability of the patient to swallow the tablet. |
? Definir la FC de naloxegol tras la administración una vez al día de múltiples dosis orales en pacientes pediátricos con EIO que siguen participando después del día 1. Se necesita un mínimo de 3 días de administración para el análisis de la FC tras dosis repetidas.
? Evaluar el grado de aceptacion de la medicación del estudio en pacientes pediátricos con EIO mediante: 1) palatabilidad de la formulación líquida y 2) capacidad del paciente de tragar el comprimido. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Patients between the ages of ? 6 months and < 18 years.
- Patients with malignant or non-malignant pain who are receiving (or are about to receive) acute or chronic treatment with opioids.
- In the investigator?s judgment, patients must be either newly diagnosed with constipation or patients must have a history of constipation treated with laxatives or are expected to develop constipation after initiation of opioid treatment.
- Female patients of childbearing potential must have a negative urine pregnancy test at screening. Females of childbearing potential must either not be sexually active or be using an adequate birth control method throughout the duration of the study. |
- Pacientes de ? 6 meses a < 18 años.
- Pacientes con dolor, neoplásico o no, que estén recibiendo (o estén a punto de recibir) un tratamiento de corta o larga duración con opioides.
- En opinión del investigador, los pacientes tienen que tener un diagnóstico reciente de estreñimiento o antecedentes de estreñimiento tratado con laxantes o se prevé que padecerán estreñimiento tras el inicio del tratamiento con opioides.
- Las mujeres en edad fértil deben tener un resultado negativo en una prueba de embarazo en orina realizada en la selección. Las mujeres potencialmente fértiles no deben ser sexualmente activas o deben usar un método anticonceptivo adecuado durante todo el ensayo. |
|
| E.4 | Principal exclusion criteria |
1. Involvement of a parent or guardian in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
2. Previous enrolment in the present study with intake of naloxegol investigational product.
3. Current acute or chronic use of methadone. For patients 6-12 months old, history of major corrective or reconstructive gastrointestinal surgery (except pyloric stenosis) in the last 6 months or possible need for corrective or reconstructive gastrointestinal surgery in the next month, or history of post-surgical ileus. For patients over 1 year of age, history of previous gastrointestinal surgery in the last 6 months (does not include placement of enteral tubes or liver biopsies).
4. History of an intra-abdominal or peritoneal neoplasm or an ongoing GI-related issue (e.g., inflammatory bowel disease, connective tissue disorders like Ehler Danlos, dermatomyositis, scleroderma) which, in the opinion of the investigator, may be contributing to constipation as a result of mechanical obstruction or may place the patient at increased risk for intestinal perforation by impairing the local or global structural integrity of the GI tract.
5. Signs or symptoms of GI obstruction including faecal impaction requiring medical intervention. History of GI obstructive conditions (e.g. Hirschsprung?s disease, malrotation, volvulus, pseudo-obstruction syndromes).
6. Currently active medical conditions or ongoing treatments (e.g. irinotecan) that may result in diarrhoea or intermittent loose stools during the screening or treatment period.
7. Need for mechanical ventilation, haemodynamic instability or other significant cardiorespiratory dysfunction.
8. Evidence of known widespread cancer metastases in the CNS.
9. Radiotherapy between the diaphragm and the pelvis in the 4 weeks prior to screening or planned to be initiated during the treatment period.
10.Any of the following findings and/or conditions:
(a) For patients 6 -12 months old, any elevation of serum direct or indirect bilirubin and LFTs that have not undergone a medical work up. For patients over 1 year old, serum ALT or AST >2.5 x upper limit of normal (ULN) and/or serum bilirubin >1.2 x ULN (unless known to be due to Gilbert?s syndrome).
(b)Creatinine clearance less than 90 ml/min/1.73 m2 (using the Shwartz formula*).
(c) Absolute neutrophil count (ANC) <0.5 x 10^9/L; haemoglobin <9 g/dL or, platelet count < 50,000/uL at the time of the first dose of naloxegol.
11. History (within past 3 months) of prolonged (> 10 days) neutropenia or thrombocytopenia with clinical sequelae.
12. Treatment with another experimental medication for which there is no current labelled therapy (adult or paediatric), currently or within the last 30 days.
13. Patients with cancer currently receiving the first cycle of chemotherapy, or due to receive a chemotherapeutic agent for the first time.
14. Life expectancy of < 3 months. |
1. Implicación del progenitor o tutor en la planificación y/o realización del ensayo (aplicable al personal de AstraZeneca y/o al personal del centro del ensayo).
2. Inclusión previa en este ensayo habiendo tomado el producto en investigación naloxegol.
3. Uso actual de metadona de corta o larga duración. En los pacientes de 6 a 12 meses de edad, antecedentes de cirugía digestiva correctora o reparadora (excepto estenosis pilórica) en los 6 últimos meses o posible necesidad de cirugía digestiva correctora o reparadora en el mes siguiente o antecedentes de íleo posquirúrgico. En los pacientes mayores de 1 año, antecedentes de cirugía digestiva previa en los 6 últimos meses (no incluye la colocación de sondas intestinales o biopsias hepáticas).
4. Antecedentes de una neoplasia intraabdominal o peritoneal o presencia actual de un problema relacionado con el aparato digestivo (p. ej., enfermedad inflamatoria intestinal, trastornos del tejido conjuntivo como el síndrome de Ehler Danlos, dermatomiositis, escleroderma) que, en la opinión del investigador, pudieran contribuir al estreñimiento como consecuencia de obstrucción mecánica o pudieran suponer para el paciente mayor riesgo de perforación intestinal al afectar a la integridad estructural local o general del tubo digestivo.
5. Signos y síntomas de obstrucción del tubo digestivo, incluida la impactación fecal que precisa intervención médica. Antecedentes de trastornos GI obstructivos (p. ej., enfermedad de Hirschsprung, malrotación, vólvulos, síndromes pseudoobstructivos).
6. Enfermedades médicas actualmente activas o tratamientos en curso (p. ej., irinotecán) que puedan producir diarrea o heces blandas intermitentes durante la selección o el período de tratamiento.
7. Necesidad de respiración mecánica, inestabilidad hemodinámica u otra disfunción cardiorrespiratoria importante.
8. Constancia de metástasis generalizadas en el SNC.
9. Radioterapia entre el diafragma y la pelvis en las 4 semanas previas a la selección o está previsto iniciarla durante el periodo de tratamiento.
10. Cualquiera de los siguientes hallazgos o trastornos:
(a) En pacientes de 6 a 12 meses de edad, cualquier elevación de la bilirrubina directa o indirecta en suero y de las pruebas de función hepática que no hayan sido objeto un estudio diagnóstico. En pacientes de más de 1 año, ALT o AST séricas > 2,5 veces el límite superior de la normalidad (LSN) y/o bilirrubina sérica 1,2 veces el LSN (salvo que se sepa que es debida a un síndrome de Gilbert).
(b) Aclaramiento de creatinina inferior a 90 ml/min/1,73 m2 (mediante la fórmula de Shwartz*).
(c) Recuento absoluto de neutrófilos (RAN) <0,5 x 10^9/l; hemoglobina <9 g/dl o recuento de plaquetas < 50.000/µl en el momento de administrar la primera dosis de naloxegol.
11. Antecedentes (en los 3 meses anteriores) de neutropenia prolongada (> 10 días) o trombocitopenia con secuelas clínicas.
12. Tratamiento actual o en los 30 días previos con otra medicación experimental para la que no exista en la actualidad un tratamiento autorizado (en adultos o pediátrico).
13. Pacientes con cáncer que han recibido el primer ciclo de quimioterapia o van a recibir un antineoplásico por primera vez.
14. Esperanza de vida ? 3 meses |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Standard non-compartmental analysis approach: area under the plasma concentration-time curve from zero extrapolated to infinity (AUC), area under the plasma concentration-time curve from zero to the last quantifiable concentration (AUC(0-t)), maximum plasma concentration (Cmax), terminal half-life (t1/2?z), time to maximum plasma concentration (tmax), and mean residence time (MRT), oral clearance (CL/F), volume of distribution during the terminal phase (Vz), and apparent volume of distribution at steady state (Vss/F).
Population pharmacokinetic modelling approach: population estimated structural PK parameters and influence of potential covariates |
Método de análisis estándar no compartimental: área bajo la curva de concentración plasmática-tiempo, extrapolada entre cero e infinito (AUC), área bajo la curva de concentración plasmática-tiempo desde cero hasta la última concentración cuantificable (AUC(0-t)), concentración plasmática máxima (Cmax), semivida terminal (t1/2?z), tiempo hasta la concentración plasmática máxima (tmax), tiempo medio de permanencia (TMP), aclaramiento oral (CL/F), volumen de distribución durante la fase terminal (Vz), y volumen de distribución aparente en estado de equilibrio (Vss/F).
Método de creación del modelo farmacocinético poblacional: cálculo de los parámetros farmacocinéticos estructurales poblacionales (es decir, CL/F, V/F y otros parámetros si procede) e influencia de posibles covariables |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 hour PK blood sampling after first dose and on day 7 |
| Determinacion de curva PK en las primeras 24 horas tras la 1ª dosis y en el dia 7. |
|
| E.5.2 | Secondary end point(s) |
| Other additional multiple dose PK parameters, e.g., RAC(AUC) and Rac(Cmax). |
| Determinacion de parametros de farmacocinetica tras dosis múltiple. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 24 hour PK blood sampling after first dose and on day 7 |
| Determinacion de curva PK en las primeras 24 horas tras la 1ª dosis y en el dia 7. |
|
| 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 | No |
| 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 | Yes |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 10 |
| 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 |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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