| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Anemia associated with chronic kidney disease |
| Anemia asociada a enfermedad renal crónica |
|
| E.1.1.1 | Medical condition in easily understood language |
| Anemia associated with chronic kidney disease |
| Anemia asociada a enfermedad renal crónica |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Physiological processes [G07] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064848 |
| E.1.2 | Term | Chronic kidney disease |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| 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 compare daprodustat to rhEPO for Hgb efficacy (non-inferiority) |
| Comparar daprodustat con EPO rHu en cuanto a eficacia de Hgb (no inferioridad). |
|
| E.2.2 | Secondary objectives of the trial |
| To compare daprodustat to rhEPO on the use of intravenous (IV) iron |
Comparar daprodustat con EPO rHu respecto al uso de hierro
intravenoso (IV) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply at screening and randomization (Day 1) unless otherwise specified.
1. Age (confirm at screening): 18 to 99 years of age inclusive
2. Dialysis: Planning to start chronic dialysis within the next 4 weeks (from the date of the screening visit) OR have started and received dialysis (as specified below) for end-stage renal disease for a maximum of ≤90 days immediately prior to randomization and is not expected to stop dialysis during the duration of the trial:
- HD ≥ 2X/week, or
- Daily PD (Including continuous and automated PD)
3. Hemoglobin concentration as measured by HemoCue (range inclusive): 8-10.5 g/dL (5-6.5 mmol/L) at screening and 8-11.0 g/dL (5-6.8 mmol/L) at randomization
4. Informed consent: capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol
Note: The country-specific requirements for France ONLY for the informed consent process is provided in Appendix 11 (see Section 12.11.1, Item 3 for details)
5. Other study eligibility criteria considerations: The country-specific requirements for France ONLY for the eligibility for inclusion in this study is provided in Appendix 11 (see Section 12.11.1, Item 1 for details) |
Un paciente solamente podrá participar en este estudio si cumple todos los criterios siguientes en la selección y la aleatorización (día 1), a menos que se especifique lo contrario.
1. Edad (confirmar en la selección): 18 a 99 años, ambos inclusive.
2. Diálisis: que planee iniciar la diálisis crónica durante las 4 semanas siguientes (desde la fecha de la visita de selección) O que haya iniciado y recibido diálisis (como se especifica a continuación) para la enfermedad
renal en su etapa final durante, como máximo, ≤90 días inmediatamente antes de la aleatorización y que no prevea interrumpir la diálisis mientras dure el ensayo:
•HD ≥ 2 veces/semana o
•PD diaria (incluida la PD continua y automatizada)
3. Concentración de hemoglobina medida mediante HemoCue (rango inclusivo): 8-10,5 g/dL (5-6,5 mmol/L) en la selección y 8-11,0 g/dL (56,8 mmol/L) en la aleatorización
4.Consentimiento informado: capaz de proporcionar un consentimiento informado firmado que incluya el cumplimiento de los requisitos y las restricciones enumeradas en el formulario de consentimiento y en este
protocolo. |
|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for participation in this study if any of the following criteria apply at screening or at randomization (Day 1), unless otherwise specified.
CKD-related criteria
1. Kidney transplant: Planned living-related donor kidney transplant during the study.
Anemia related criteria
2. Ferritin: ≤100 ng/mL (≤100 µg/L) at screening or after IV iron supplementation.
3. TSAT: ≤20% at screening or after IV iron supplementation.
4. Vitamin B12: Below the lower limit of the reference range at screening or after vitamin B12 supplementation
5. Folate: <2.0 ng/mL (<4.5 nmol/ L) at screening
6. Aplasias: History of bone marrow aplasia or pure red cell aplasia (PRCA).
7. Other causes of anemia: Pernicious anemia, thalassemia major, sickle cell disease, or myelodysplastic syndrome.
8. Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease OR clinically significant GI bleeding ≤10 weeks prior to screening through to randomization (Day 1).
Erythropoiesis treatment criteria
9. Use of any ESA treatment within 8 weeks prior to screening except for limited use as part of dialysis initiation. Limited use is defined as no more than 6 weeks of short acting ESA (rhEPO or biosimilars; maximum of 20000 U total) or long acting ESA (darbepoetin alfa [maximum of 100 µg total] or methoxy polyethylene glycol-epoetin beta [maximum of 125 µg total]) received before or after starting dialysis.
Cardiovascular disease-related criteria
10. Myocardial infarction or acute coronary syndrome: ≤10 weeks prior to screening through to randomization (Day 1).
11. Stroke or transient ischemic attack: ≤10 weeks prior to screening through to randomization (Day 1).
12. Heart failure: Chronic Class IV heart failure, as defined by the New York HeartAssociation (NYHA) functional classification system.
13. Current uncontrolled hypertension: Current uncontrolled hypertension as determined by the Investigator that would contraindicate the use of rhEPO.
14. QTcB (Day 1): QTcB >500 msec, or QTcB >530 msec in subjects with bundle branch block. There is no QTc exclusion for subjects with a predominantly paced rhythm
Other disease-related criteria
15. Liver disease (any one of the following):
- Alanine transaminase (ALT) >2x upper limit of normal (ULN) (screening only)
- Bilirubin >1.5xULN (screening only)
NOTE: Isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%.
- Current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
NOTE: Stable chronic liver disease (including asymptomatic gallstones, chronic hepatitis B or C, or Gilbert's syndrome) are acceptable if subjectotherwise meets entry criteria.
16. Malignancy: History of malignancy within the 2 years prior to screening through to randomization (Day 1), or currently receiving treatment for cancer, or complex kidney cyst (i.e. Bosniak Category II F, III or IV) > 3cm. The only exception is localized squamous cell or basal cell carcinoma of the skin that has been definitively treated ≥10 weeks prior to screening. Concomitant medications and other study treatment-related criteria
17. Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product (refer to daprodustat IB) or to darbepoetin alfa (refer to product labelling)
18. Drugs and supplements (randomization only): Use of strong CYP2C8 inhibitors (e.g., gemfibrozil) or strong CYP2C8 inducers (e.g., rifampin/rifampicin).
19. Prior investigational product exposure: Use of an investigational drug (other than daprodustat – see next criterion) ≤30 days or within five half-lives of the investigational agent, whichever is longer prior to screening.
20. Prior treatment with daprodustat: Any prior treatment with daprodustat for treatment duration of > 30 days.
General health-related criteria
21. Females ONLY: Subject is pregnant [as confirmed by a positive serum human chorionic gonadotropin (hCG) test for females of reproductive potential (FRP) only], subject is breastfeeding, or subject is of reproductive potential and does not agree to follow one of the contraceptive options in the List of Highly Effective Methods for Avoiding Pregnancy listed in Appendix 5.
22. Other Conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the subject at unacceptable risk, which may affect study compliance (e.g., intolerance to rhEPO) or prevent understanding of the aims or investigational procedures or possible consequences of the study. |
Criterios relacionados con la ERC
1.Trasplante de riñón: previsión de trasplante de riñón de donante vivo relacionado durante el estudio.
Criterios relacionados con la anemia
2.Ferritina: 100 ng/mL (100 g/L) en la selección o después de la aportación suplementaria de hierro IV.
3.TSAT: 20 % en la selección o después de la aportación suplementaria de hierro IV.
4.Vitamina B12: por debajo del límite inferior del intervalo de referencia en la selección o después de la aportación suplementaria de vitamina B12
5.Folato: <2,0 ng/mL (<4,5 nmol/ L) en la selección
6.Aplasias: antecedentes de aplasia de médula ósea o aplasia pura de serie roja.
7.Otras causas de anemia: anemia perniciosa, talasemia mayor, enfermedad de células falciformes o síndrome mielodisplásico.
8.Sangrado gastrointestinal: evidencia de sangrado gástrico, duodenal o úlcera esofágica O sangrado GI clínicamente significativo ≤10 semanas antes de la selección hasta la aleatorización (día 1).
Criterios de tratamiento de la eritropoyesis
9.Uso de cualquier tratamiento con AEE durante las 8 semanas
anteriores a la selección, excepto el uso limitado como parte del inicio de la diálisis. El uso limitado se define como no más de 6 semanas de AEE de acción breve (EPO rHu o biosimilares; máximo de 20 000 U en total) o
AEE de acción larga (darbepoetina alfa [máximo de 100 g en total] o metoxi-polietilenglicol epoetina beta [máximo de 125 g en total]) recibidos antes o después de iniciar la diálisis.
Criterios relacionados con la enfermedad cardiovascular
10. Infarto de miocardio o síndrome coronario agudo: ≤10 semanas
antes de la selección hasta la aleatorización (día 1).
11. Ictus o accidente isquémico transitorio: ≤10 semanas antes de la selección hasta la aleatorización (día 1).
12. Fallo cardíaco: fallo cardíaco de clase IV crónico, según la definición del sistema de clasificación funcional de la NYHA.
13. Hipertensión incontrolada actual: hipertensión incontrolada actual, de acuerdo con lo que establezca el investigador, que contraindique el uso de EPO rHu.
14. QTcB (día 1): QTcB >500 msec, o QTcB >530 ms en pacientes con bloqueo de rama. No hay exclusión de QTc para los pacientes que tengan un ritmo predominantemente regular
Otros criterios relacionados con la enfermedad
15. Enfermedad hepática (cualquiera de las siguientes):
• Alanina transaminasa (ALT) >2 x el límite superior de la normalidad
(LSN) (solo selección)
• Bilirrubina >1,5 x LSN (solo selección). La bilirrubina aislada >1,5 x
LSN es aceptable si la bilirrubina es fraccionada y la bilirrubina directa <35 %.
• Enfermedad hepática o biliar actual inestable según la evaluación del
investigador, definida en general por la presencia de ascitis, encefalopatía, coagulopatía, hipoalbuminemia, varices esofágicas o gástricas, ictericia persistente o cirrosis. NOTA: La enfermedad hepática
crónica estable son aceptables.
16. Neoplasia maligna: antecedentes de neoplasia maligna durante los 2 años anteriores a la selección y hasta la aleatorización (día 1), o recibir actualmente tratamiento para el cáncer o quiste de riñón complejo (categoría Bosniak II F, III o IV) > 3 cm. La única excepción es el carcinoma localizado de células escamosas o basocelular en la piel cuyo tratamiento haya finalizado de manera definitiva 10 semanas antes de la selección.
Medicamentos concomitantes y otros criterios relacionados con el
tratamiento del estudio
17. Reacciones alérgicas graves: antecedentes de reacciones alérgicas o anafilácticas graves o hipersensibilidad a excipientes presentes en el producto en investigación o a darbepoetina alfa
18. Fármacos y suplementos (solo aleatorización): uso de inhibidores fuertes de CYP2C8 o inductores fuertes de CYP2C8.
19. Exposición anterior al producto en investigación: uso de un fármaco en investigación (diferente de daprodustat, consulte el siguiente criterio) en un plazo de 30 días o cinco semividas del agente en
investigación, lo que sea más largo, antes de la selección.
20. Tratamiento previo con daprodustat: cualquier tratamiento anterior con daprodustat mientras dure el tratamiento de > 30 días.
Criterios relacionados con la salud en general
21. SOLO para mujeres: la paciente está embarazada (como se confirma a través de una prueba positiva de gonadotropina coriónica humana [hCG] en suero solo para mujeres con potencial reproductivo [FRP por
sus siglas en ingl.]), está amamantando o tiene potencial reproductivo y no acepta seguir una de las opciones anticonceptivas que figuran en la Lista de métodos altamente eficaces para evitar el embarazo del Apéndice 5.
22. Otras enfermedades: cualquier otra enfermedad, anomalía clínica o analítica o resultado de examen que, según el criterio del investigador, pueda suponer un riesgo inaceptable para el paciente, que pueda afectar
a la adecuación al estudio o que impida entender los objetivos, los procedimientos de la investigación o las posibles consecuencias del estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Mean change in Hgb between baseline and evaluation period (EP, mean over Weeks 28-52) |
El cambio medio que se produzca en la Hgb desde el inicio y el periodo
de evaluación (PE, media a lo largo de las semanas 28-52). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Between week 28 and week 52 |
| Entre semana 28 y semana 52. |
|
| E.5.2 | Secondary end point(s) |
| Average monthly IV iron dose (mg)/subject from baseline to Week 52 |
Dosis mensual media de hierro IV (mg) /paciente desde el inicio hasta la
semana 52 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Between baseline and Week 52 |
| Entre el inicio y la semana 52 |
|
| 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 | No |
| 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) | 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 | 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 | Yes |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| France |
| Germany |
| India |
| Italy |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Poland |
| Russian Federation |
| South Africa |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| Last visit of the last subject |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 7 |
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