E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Male or female, 18 years of age or older who have received an allogeneic hematopoietic stem cell transplant (allo-HSCT) and have developed Grade II to IV acute GVHD |
Varones o mujeres, de 18 años en adelante que hayan recibido un alotrasplante de células madre hematopoyéticas (ATCMH) y hayan presentado EICHa de grado II a IV |
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E.1.1.1 | Medical condition in easily understood language |
Acute graft versus host disease after allogeneic stem cell transplantation |
Enfermedad de injerto contra huésped en fase aguda tras el trasplante alogénico de células madre |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066260 |
E.1.2 | Term | Acute graft versus host disease |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066262 |
E.1.2 | Term | Acute graft versus host disease in skin |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066264 |
E.1.2 | Term | Acute graft versus host disease in intestine |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066263 |
E.1.2 | Term | Acute graft versus host disease in liver |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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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 |
Compare the efficacy of itacitinib in combination with corticosteroids versus placebo in combination with corticosteroids in terms of overall response rate (ORR) at Day 28 in subjects with acute graft-versus-host disease (aGVHD). |
Comparar la eficacia de itacitinib en combinación con corticosteroides frente a placebo en combinación con corticosteroides en lo que respecta a la tasa de respuesta global (TRG) el día 28 en sujetos con enfermedad de injerto contra huésped en fase aguda (EICHa). |
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E.2.2 | Secondary objectives of the trial |
- Compare the efficacy between treatment cohorts at a subsequent key clinical landmark (key secondary objective). - Compare additional response and longer-term efficacy outcomes between treatment cohorts. - Assess the incidence and severity of adverse events (AEs) and serious adverse events. - Evaluate the pharmacokinetics of itacitinib when administered in combination with corticosteroids. - Evaluate the incidence of secondary graft failure. - Evaluate the use and discontinuation of corticosteroids. - Evaluate the use and discontinuation of immunosuppressive medications. - Evaluate the incidence of aGVHD flares. - Evaluate the incidence of cGVHD. |
- Comparar la eficacia entre las cohortes de tratamiento en un momento clínico clave posterior. - Comparar variables de eficacia a largo plazo y de respuesta adicionales entre las opciones de tratamiento. - Evaluar la incidencia e intensidad de los acontecimientos adversos (AA) y los acontecimientos adversos graves. - Evaluar la farmacocinética de itacitinib cuando se administra en combinación con corticosteroides. - Evaluar la incidencia de fracaso secundario del injerto. - Evaluar el uso y la suspensión del tratamiento con corticosteroides. - Evaluar el uso y la suspensión del tratamiento con inmunosupresores. - Evaluar la incidencia de brotes de la EICHa. - Evaluar la incidencia de EICHc. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male or female, 18 years of age or older. • Has undergone 1 allo-HSCT from any donor (related or unrelated with any degree of HLA matching) and any donor source (bone marrow, peripheral blood stem cells, or cord blood) for a hematologic malignancy or disorder. Recipients of myeloablative and reduced-intensity conditioning regimens are eligible. • Clinically suspected Grade II to IV aGVHD as per MAGIC criteria, occurring after allo-HSCT and any GVHD prophylaxis regimen. Biopsies should be obtained to pathologically confirm aGVHD; in cases where a biopsy is negative, is unable to be obtained, or is clinically contraindicated, clinical suspicion of aGVHD by the treating physician is sufficient, provided that alternative diagnoses of drug effects or infection are adequately ruled out. • Evidence of myeloid engraftment (eg, absolute neutrophil count ≥ 0.5 × 109/L for 3 consecutive days if ablative therapy was previously used). Use of growth factor supplementation is allowed. |
• Varones o mujeres, de 18 años en adelante. • Haber recibido un ATCMH de cualquier donante (emparentado o no emparentado, con cualquier grado de histocompatibilidad) y cualquier fuente donante (médula ósea, células madre de sangre periférica o cordón umbilical) para un trastorno o neoplasia maligna hematológicos. Son elegibles los receptores de regímenes de acondicionamiento mieloablativo y de intensidad reducida. • Sospecha clínica de EICHa de grado II a IV según los criterios MAGIC con posterioridad al ATCMH y cualquier tratamiento profiláctico contra la EICH. Deben realizarse biopsias para la confirmación anatomopatológica de la EICHa; cuando la biopsia indique que no hay EICH, no pueda realizarse o esté contraindicada clínicamente, la sospecha clínica de EICHa por el médico responsable del tratamiento será suficiente, siempre que se descarten adecuadamente diagnósticos alternativos de efectos farmacológicos o infección. • Signos de prendimiento mieloide del injerto (p. ej., recuento absoluto de neutrófilos ≥0,5 × 109/l durante tres días consecutivos si se usó previamente tratamiento mieloablativo). Se permite el uso de factores de crecimiento de forma complementaria. |
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E.4 | Principal exclusion criteria |
• Has received more than 1 allo-HSCT. • Has received more than 2 days of systemic corticosteroids for acute-GVHD. • Presence of GVHD overlap syndrome. • Presence of an active uncontrolled infection. |
• Haber recibido más de un ATCMH. • Haber recibido corticosteroides sistémicos durante más de 2 días contra la EICHa. • Presencia de síndrome de superposición relativo a la EICH. • Presencia de una infección activa y no controlada. |
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E.5 End points |
E.5.1 | Primary end point(s) |
ORR at Day 28, defined as the proportion of subjects demonstrating a complete response (CR), very good partial response (VGPR), or partial response (PR). |
TRG el día 28, definida como el porcentaje de sujetos que demuestran respuesta completa (RC), respuesta parcial muy buena (RPMB) o respuesta parcial (RP). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- NRM at Month 6, defined as the proportion of subjects who died due to causes other than malignancy relapse at Month 6 (key secondary endpoint). - ORR, defined as the proportion of subjects demonstrating a CR, VGPR, or PR at Days 14, 56, and 100. - NRM at Months 9, 12, and 24. - Duration of response, defined as the interval from first response until graft-versus-host disease (GVHD) progression or death. - Time to response, defined as the interval from treatment initiation to first response. - Malignancy relapse rate, defined as the proportion of subjects whose underlying malignancy relapses. - Malignancy relapse-related mortality rate, defined as the proportion of subjects whose malignancy relapses and has a fatal outcome. - Failure-free survival, defined as the proportion of subjects who are still alive, have not relapsed, have not required additional therapy for aGVHD, and have not demonstrated signs or symptoms of chronic graft-versus-host disease (cGVHD), at Month 6. - Overall survival (OS), defined as the interval from study enrollment to death due to any cause. - Clinical safety data (eg, AEs, infections) will be tabulated and listed. - Cmax, Cmin, tmax, AUC, and CL/F. - Incidence rate of secondary graft failure, defined as > 95% recipient cells any time after engraftment with no signs of relapse, OR retransplantation because of secondary neutropenia (< 0.5 × 109/L) and/or thrombocytopenia (< 20 × 109/L) within 2 months of transplant. - Average and cumulative corticosteroid dose at Days 28, 56, 100, and 180; proportion of subjects who discontinue corticosteroids at Days 56 and 100. - Proportion of subjects who discontinue immunosuppressive medications at Days 56 and 100. - Incidence rate of aGVHD flares through Day 100. - Incidence rate of cGVHD at Days 180 and 365. |
- Mortalidad sin recidiva (MSR) en el mes 6, definida como el porcentaje de sujetos que fallecen por causas distintas de una recidiva de la neoplasia maligna en el sexto mes. - TRG, definida como el porcentaje de sujetos que demuestran RC, RPMB o RP los días 14, 56 y 100. - MSR en los meses 9, 12 y 24. - Tiempo transcurrido hasta la respuesta, definida como el intervalo transcurrido desde la instauración de la respuesta hasta la primera respuesta. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day 14, 28, 56, 100 Months 6, 9, 12 and 24 |
Día 14, 28, 56, 100 Meses 6, 9, 12 and 24 |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
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 |
Australia |
Canada |
Israel |
Korea, Republic of |
New Zealand |
Singapore |
Switzerland |
Taiwan |
Turkey |
United States |
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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
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The study will end once 75% of subjects have achieved 2-year transplant-related mortality, have died, or have been lost to follow-up.
An end of the trial can not be determined as each subject enrolled in the study may continue to receive study treatment as long as benefit is being observed and/or treatment withdrawal criteria are not met. |
El estudio terminará cuando el 75 % de los sujetos haya alcanzado la mortalidad a los 2 años relacionada con el trasplante, haya fallecido o se haya perdido el contacto con ellos durante el seguimiento.
No se puede determinar el final del ensayo, ya que cada sujeto inscrito en el estudio puede seguir recibiendo tratamiento del estudio mientras se observe el beneficio y / o no se cumplan los criterios de retirada del tratamiento. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |