| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| transfusion-dependent thalassemia or myelodysplastic syndrome at very low, low or intermediate (int-1) risk |
| talasemia dependiente de transfusiones o síndrome mielodisplásico a muy baja, baja o intermedia (int-1) riesgo |
|
| E.1.1.1 | Medical condition in easily understood language |
| transfusion-dependent thalassemia or myelodysplastic syndrome |
| talasemia dependiente de transfusiones o síndrome mielodisplásico |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| 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 | 10054658 |
| E.1.2 | Term | Thalassemia |
| E.1.2 | System Organ Class | 100000004850 |
|
| 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 | 10028534 |
| E.1.2 | Term | Myelodysplastic syndrome NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 evaluate the overall safety of deferasirox FCT and deferasirox DT formulations in patients with transfusion-dependent thalassemia or myelodysplastic syndrome at low or intermediate (int-1) risk. |
| Evaluar la seguridad global de las formulaciones de deferasirox FCT y de deferasirox DT en pacientes con síndrome mielodisplásico de riesgo muy bajo, bajo o intermedio (int) o talasemia dependiente de transfusión |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate both formulations on selected GI AEs
- To evaluate pharmacokinetics of both formulations
- To evaluate both formulations on patient satisfaction and palatability using a Patient Reported Outcomes (PRO) questionnaire
- To evaluate both formulations on patient?s GI symptoms using a PRO daily diary
- To evaluate both formulations on patient compliance using pill count and a PRO daily diary |
? Evaluar ambas formulaciones en AAs de GI seleccionados
? Evaluar la farmacocinética de ambas formulaciones
? Evaluar ambas formulaciones en la satisfacción del paciente y en la palatabilidad utilizando un cuestionario de resultados notificados por el paciente (PRO)
? Evaluar la farmacocinética de ambas formulaciones
? Evaluar ambas formulaciones en los síntomas GI del paciente utilizando un diario de PRO completado diariamente
? Evaluar ambas formulaciones en el cumplimiento del paciente utilizando recuento de comprimidos y el diario de PRO diario. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent/assent before any study-specific procedures. For pediatric patients, consent will be obtained from parent(s) or legal patient?s representative. Investigators will also obtain assent of patients according to local, regional or national guidelines.
2. Male and female patients aged ? 10 years
3. Patients with transfusion-dependent thalassemia and iron overload, requiring deferasirox DT at doses of ? 30 mg/kg/day as per the investigator?s decision
OR
Patients with very low, low or intermediate (int-1) risk myelodysplastic syndrome (MDS) and iron overload, requiring deferasirox DT at doses of ? 20 mg/kg/day as per the investigator?s decision.
? The very low, low or intermediate (int-1) risk MDS should be determined by the Revised International Prognostic Scoring System (IPSS-R) and IPSS-R must be confirmed by a bone marrow examination within 6 months prior to study entry and must be hematologically stable with a patient?s life expectancy of at least 1 year.
4. History of transfusion of at least 20 PRBC units and anticipated to be transfused with at least 8 units of PRBCs annually during the study
5. Serum ferritin > 1000 ng/mL, measured at screening Visit 1 and screening Visit 2 (the mean value will be used for eligibility criteria) |
? Consentimiento/asentimiento informado por escrito antes de cualquier procedimiento específico del estudio. Para los pacientes pediátricos, el consentimiento se obtendrá del(la) padre/madre o del representante legal del paciente. Los investigadores también obtendrán el asentimiento del paciente según las pautas locales, regionales o nacionales.
? Hombres y mujeres con ? 10 años
? Pacientes con talasemia dependiente de transfusión y sobrecarga de hierro, que precisen deferasirox DT a dosis de ? 30 mg/kg/día, a criterio del investigador.
? Pacientes con síndrome mielodisplásico (SMD) de riesgo muy bajo, bajo o intermedio y sobrecarga de hierro que precisen deferasirox DT a dosis de ? 20 mg/kg/día, a criterios del investigador
? El SMD de riesgo muy bajo, bajo o intermedio (int) debería determinarse con el sistema de puntuación pronóstico internacional revisado (IPSS-R) e el IPSS-R deberá confirmarse con un examen de médula ósea dentro de los 6 meses antes de entrar en el estudio y deberán permanecer hematológicamente estables con una esperanza de vida del paciente de por lo menos 1 año.
? Antecedentes de transfusión de por lo menos 20 unidades de PRBC y que se prevea que recibirán transfusiones con por lo menos 8 unidades de PRBCs anualmente durante el estudio.
? Ferritina sérica > 1000ng/mL, medido en la visita 1 de selección y en la visita 2 de selección (el valor medio se utilizará para los criterios de elegibilidad). |
|
| E.4 | Principal exclusion criteria |
1. Creatinine clearance below the contraindication limit in the locally approved prescribing information. Creatinine clearance will be estimated from serum creatinine at screening Visit 1 and screening Visit 2 and the mean value will be used for eligibility criteria.
2. Serum creatinine > 1.5 xULN at screening measured at screening Visit 1 and screening Visit 2 (the mean value will be used for eligibility criteria).
3. ALT (SGPT) > 5xULN, unless if LIC confirmed as <10 mg Fe/dw within 6 months prior to screening visit 1.
4. Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a non-first void urine sample at screening Visit 1 or screening Visit 2.
5. Patients with significant impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral deferasirox (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
6. Clinical or laboratory evidence of active Hepatitis B or Hepatitis C (HBsAg in the absence of HBsAb OR HCV Ab positive with HCV RNA positive).
7. Patients with psychiatric or addictive disorders which prevent them from giving their informed consent or undergoing any of the treatment options or patients unwilling or unable to comply with the protocol (including use of electronic devices for ePRO).
8. Patients with a known history of HIV seropositivity (Elisa or Western blot).
9. History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin.
10. Patients participating in another clinical trial or receiving an investigational drug.
11. History of hypersensitivity to any of the study drug or excipients.
12. Significant medical condition interfering with the ability to partake in this study (e.g. systemic uncontrolled hypertension, unstable cardiac disease not controlled by standard medical therapy, systemic disease (cardiovascular, renal, hepatic, etc.).
13. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment.
14. Sexually active males unless they use a condom during intercourse while taking drug and
for 28 days after stopping study medication and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. |
? Aclaramiento de creatinina por debajo del límite de contraindicación en la información de prescripción localmente aprobada. El aclaramiento de creatinina se calculará a partir de la creatinina sérica en la visita 1 y en la visita 2 de selección y el valor medio se utilizará para los criterios de elegibilidad.
? Creatinina sérica > 1.5 x LSN en la selección, medido en la visita 1 y en la visita 2 de selección (el valor medio se utilizará para los criterios de elegibilidad).
? ALT (SGPT) > 5 x LSN, excepto si la LIC confirmada como <10 mg Fe/dw dentro de los 6 meses antes de la visita de selección 1.
? Proteinuria significativa indicada con una proporción de proteína/creatinina urinaria >0.5 mg/mg en una muestra de orina no de primera micción en la visita de selección 1 y en la visita de selección 2.
? Pacientes con deterioro significativo de la función gastrointestinal (GI) o enfermedad GI que pueda alterar significativamente la absorción de deferasirox oral (por ejemplo, enfermedades ulcerosas, náuseas incontroladas, vómitos, diarrea, síndrome de mala absorción o resección del intestino delgado.
? Evidencia clínica o de laboratorio de Hepatitis B o de Hepatitis C activa (HBsAg en ausencia de HBsAb O VHC Ab positivo con ARN del VHC positivo)
? Pacientes con alteraciones psiquiátricas o adictivas que impidan que otorguen su consentimiento informado o que reciban alguna de las opciones de tratamiento o pacientes que no quieran o no puedan cumplir con el protocolo (incluyendo el uso de los dispositivos electrónicos para el PROe). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall safety, as measured by frequency and severity of adverse events and changes in laboratory values from baseline (serum creatinine, creatinine clearance, ALT, AST, platelets, RBC and WBC) |
| Seguridad total, medido por la frecuencia y gravedad de los eventos adversos y los cambios en los valores de laboratorio de la línea de base (creatinina sérica, aclaramiento de creatinina, ALT, AST, plaquetas, glóbulos rojos y glóbulos blancos) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| weekly for first 4 weeks and then every 4 weeks until end of treatment |
| semanalmente durante las primeras 4 semanas y luego cada 4 semanas hasta finalizar el tratamiento |
|
| E.5.2 | Secondary end point(s) |
1) Frequency of selected GI AEs (diarrhea, constipation, nausea, vomiting, abdominal pain)
2) PK parameters
3) Domain scores of treatment satisfaction and palatability over time
4) Weekly average of daily scores of GI diary
5) Relative consumed FCT/DT counts
6) Patient-reported medication consumption |
1) Frecuencia de las reacciones adversas seleccionadas GI (diarrea, estreñimiento, náuseas, vómitos, dolor abdominal)
2) los parámetros farmacocinéticos
3) las puntuaciones de dominio de satisfacción con el tratamiento y la palatabilidad en el tiempo
4) la media semanal de las puntuaciones diarias del diario GI
5) los recuentos de FCT / DT relativa consumidos
6) El consumo de medicamentos en el paciente informado |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) weekly for first 4 weeks and then every 4 weeks until end of treatment
2) ? AUCtau, AUClast, Cmax, Tmax at week 1 and week 3 (only applies to PK subset A)
? C2hr and Ctrough at week 3, 13 and 21 for all study patients
3) week 2, 3 and 13and last day of treatment
4) daily completion of questionnaire until last day of treatment
5) monthly
6) daily completion of questionnaire until last day of treatment |
1) por semana durante las primeras 4 semanas y luego cada 4 semanas hasta finalizar el tratamiento
2) ? AUCtau, AUCúlt, Cmax, Tmax en la semana 1 y la semana 3 (sólo se aplica a PK subgrupo A)
? C2hr y Cvalle en la semana 3, 13 y 21 para todos los pacientes del estudio
3) semanas 2, 3 y 13y último día de tratamiento
4) la realización diaria de cuestionario hasta último día de tratamiento
5) mensual
6) la realización diaria de cuestionario hasta el último día de tratamiento |
|
| 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 | 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) | 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 | 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 | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Belgium |
| Canada |
| France |
| Greece |
| Italy |
| Japan |
| Austria |
| Germany |
| Spain |
| Thailand |
| Tunisia |
| United Kingdom |
| United States |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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