E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
PIK3CA-related overgrowth spectrum (PROS) |
Síndrome de sobrecrecimiento asociado a PIK3CA (SSAP) |
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E.1.1.1 | Medical condition in easily understood language |
PROS is a wide group of clinically recognizable mutation-driven malformations |
SSAP es un amplio grupo de malformaciones provocadas por mutaciones clinicamente reconocibles. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10081236 |
E.1.2 | Term | PIK3CA related overgrowth spectrum |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic 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 |
Prospective period only: To assess the long-term safety and tolerability of alpelisib over time. |
Periodo prospectivo solamente: Evaluar la seguridad y la tolerabilidad a largo plazo de alpelisib |
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E.2.2 | Secondary objectives of the trial |
● Retrospective period only: To assess the safety and tolerability of alpelisib. ● Prospective period only: To assess the safety and tolerability of alpelisib over time. ● Retrospective and prospective period: To evaluate the long-term efficacy of alpelisib To assess symptoms and complications/comorbidities associated with PROS over time. To assess the frequency of healthcare visits/hospitalizations due to PROS over time. To assess type of medications and non-drug therapies over time. |
- Solo para el periodo retrospectivo: Evaluar la seguridad y la tolerabilidad de alpelisib. - Solo para el periodo prospectivo: Evaluar la seguridad y la tolerabilidad de alpelisib a lo largo del tiempo. - Periodo retrospectivo y periodo prospectivo: Evaluar la eficacia a largo plazo de alpelisib. Evaluar los síntomas y complicaciones/comorbilidades asociados al SSAP a lo largo del tiempo. Evaluar la frecuencia de las visitas médicas/hospitalizaciones por SSAP a lo largo del tiempo. Evaluar el tipo de medicación y las terapias no farmacológicas a lo largo del tiempo. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Participants who had previously participated in the study EPIK-P1. 2. Signed informed consent form and assent (when applicable) from the participant, parent, or guardian must be obtained prior to any study related screening procedures being performed. 3. Participant is treated with at least one dose of alpelisib after the EPIK-P1 study data cut-off date of 09-Mar-2020: ● If participants discontinue treatment for safety reasons prior to the first visit for the prospective period of the current study and if the treatment cannot be restarted, but they consent for the retrospective period, only the retrospective data will be abstracted ● If participants discontinue treatment for any other reason, including worsening of disease, prior to the first visit for the prospective period of the current study, and they consent to restart treatment as considered beneficial by the investigator, they are eligible for both periods |
1. Participantes que hayan participado anteriormente en el estudio EPIK-P1. 2. Debe obtenerse el formulario de consentimiento informado y asentimiento (cuando proceda) firmados del participante, progenitor o tutor antes de que se lleve a cabo cualquier procedimiento de selección relacionado con el estudio. 3. Participantes tratados con al menos una dosis de alpelisib después del día 9 de marzo de 2020, fecha de corte de datos del estudio EPIK-P1: ● Si los participantes discontinúan el tratamiento por motivos de seguridad antes de la primera visita del periodo prospectivo de este estudio y si el tratamiento no se puede reanudar, pero dan su consentimiento para el periodo retrospectivo, solo se extraerán los datos retrospectivos. ● Si los participantes discontinúan el tratamiento por cualquier otro motivo, como empeoramiento de la enfermedad, antes de la primera visita del periodo prospectivo de este estudio y si dan su consentimiento para reanudar el tratamiento considerado beneficioso por el investigador, son elegibles para ambos periodos. |
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E.4 | Principal exclusion criteria |
1. For participants in the retrospective period: All EPIK-P1 participants who permanently discontinued the investigational drug on or prior to the cut-off date 09-Mar-2020. 2. For participants in the prospective period: Previous alpelisib treatment discontinuation (after 09-Mar-2020) due to any of the following adverse events- ● Grade 4 skin and subcutaneous tissue disorders ● Stevens-Johnson-Syndrome (SJS)/ Toxic Epidermal Necrolysis (TEN) or other SJS/TEN-like severe skin reactions (any grade) ● Grade 4 hyperglycemia without confounding factors ● Pneumonitis (any grade) ● Grade 4 stomatitis ● Grade 4 pancreatitis ● Recurrent grade 4 thrombocytopenia ● Grade 3 or 4 serum creatinine increase ● Grade 4 isolated total bilirubin elevation ● Recurrent grade 3 or 4 QT interval corrected by Fridericia’s formula prolongation (>500 ms or >60 ms change from baseline) 3. For participants in the prospective period: Known impairment of GI function due to concomitant disease that may significantly alter the absorption of the study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) at time of informed consent. 4. For participants in the prospective period: Participant with uncontrolled diabetes mellitus (Type I or II) at time of informed consent. |
1. Para participantes en el periodo retrospectivo Todos los participantes del EPIK-P1 que hayan discontinuado permanentemente el fármaco en investigación el día 9 de marzo de 2020, fecha de corte de datos, o antes de esa fecha. 2. Para participantes en el periodo prospectivo Discontinuación del tratamiento anterior con alpelisib (después del 9 de marzo de 2020) debido a alguno de los siguientes acontecimientos adversos: ● Alteraciones de la piel y del tejido subcutáneo de grado 4. ● Síndrome de Stevens-Johnson (SSJ)/necrólisis epidérmica tóxica (NET) u otra reacción cutánea grave de tipo SSJ/NET (de cualquier grado). ● Hiperglucemia de grado 4 sin factores que causen confusión. ● Neumonitis (de cualquier grado). ● Estomatitis de grado 4. ● Pancreatitis de grado 4. ● Trombocitopenia de grado 4 recurrente. ● Aumento de la creatinina sérica de grado 3 o 4. ● Aumento aislado de la bilirrubina total de grado 4. ● Prolongación del intervalo QT de grados 3 o 4 recurrente corregido con la fórmula de Fridericia (cambio >500 ms o >60 ms respecto a la basal). 3. Alteración conocida de la función GI debida a enfermedad concomitante que pueda alterar significativamente la absorción del fármaco del estudio (p. ej., enfermedades ulcerosas, náuseas incontroladas, vómitos, diarrea, síndrome de mala absorción o resección del intestino delgado) en el momento del consentimiento informado. 4. Participantes con diabetes mellitus no controlada (de tipo I o II) en el momento del consentimiento informado. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of new or worsening grade >/= 3 treatment emergent AEs (by system organ class and preferred term) |
Incidencia de acontecimientos adversos de grado >/= 3 (según la clasificación por grupos y sistemas y por término preferente) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Proportion of participants with an incidence of a grade >/= 3 AE annually. Participants will be followed for at least 5 years in the prospective period of the study or until discontinuation of treatment |
Proporción de participantes con una incidencia de acontecimientos adversos de grado >/= 3 anualmente. Los participantes se les hara un seguimiento de al menos 5 años en el periodo prospectivo del estudio o hasta discontinuación de tratamiento. |
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E.5.2 | Secondary end point(s) |
Retrospective period only: ● Incidence, type and severity per common terminology criteria for AEs (CTCAE) v4.03 criteria, causality assessments of AEs, and other safety data including changes in laboratory values, vital signs and assessment of cardiac function.
Prospective period only: ● Incidence, type and severity per CTCAE v4.03 criteria, causality assessments of AEs, and other safety data including changes in laboratory values, vital signs and assessment of cardiac function. Additionally, for this period only, growth, bone/dental development and sexual maturation (for applicable age) will be assessed.
Retrospective and prospective period: ● Investigator assessment of lesion response as improved, stable or worsened. ● Incidence of PROS-related symptoms and complications/comorbidities among participants with symptoms and complications/comorbidities. ● Number of healthcare visits/hospitalizations due to PROS. ● Description of medications and non-drug therapies received: - PROS-related treatment(s) other than alpelisib ● Medication(s) (e.g., concomitant PROS-related medications including medication for the management of PROS related complications as well as medications to manage complications secondary to alpelisib) ● Non-drug treatment(s) (e.g., feeding tube, ketogenic diet, non-invasive device for sleep apnea, sclerotherapy, endovascular occlusive procedures) - Alpelisib treatment (e.g., dose, dose adjustments, duration of treatment, dose interruptions, discontinuation) - PROS-related surgeries (e.g., de-bulking or vascular surgery as well as the intended site of the procedure) |
Solo periodo retrospectivo: - Incidencia, tipo y gravedad según los criterios de terminología común para EA (CTCAE) criterios v4.03, evaluaciones de causalidad de EA y otros datos de seguridad, incluidos cambios en los valores de laboratorio, signos vitales y evaluación de la función cardíaca.
Solo periodo prospectivo: - Incidencia, tipo y gravedad según los criterios CTCAE v4.03, evaluaciones de causalidad de EA y otros datos de seguridad, incluidos cambios en los valores de laboratorio, signos vitales y evaluación de la función cardíaca. Además, solo durante este período, se evaluará el crecimiento, el desarrollo óseo / dental y la maduración sexual (para la edad aplicable).
Periodos retrospectivos y prospectivos: - Evaluación del investigador de la respuesta de la lesión como mejorada, estable o con progresión. - Evaluar los síntomas relacionados con SSAP y complicaciones / comorbilidades entre los participantes con síntomas y complicaciones / comorbilidades. - Número de visitas médicas / hospitalizaciones por SSAP.
REFIERASE AL PROTOCOLO PARA RESTO DE EVALUACIONES |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Proportion of participants with an incidence of a grade >/= 3 AE annually. Participants will be followed for at least 5 years in the prospective period of the study or until discontinuation of treatment |
Proporción de participantes con una incidencia anual de acontecimientos adversos de grado >/= 3. A los participantes se les realizará un seguimiento durante al menos 5 años en el periodo prospectivo del estudio o hasta la discontinuación del tratamiento |
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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 | 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) | 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 | 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 |
Periodo retrospectivo: no intervencionista; periodo prospectivo: intervencionista |
Retrospective period: non-interventional; prospective period: interventional |
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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 | 1 |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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 |
Ireland |
Spain |
United States |
France |
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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
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The end of the study for a given participant when the participant permanently discontinues study treatment with alpelisib and all the end of study procedures are completed (including the 30 days safety follow-up). The end of the overall study is defined as the time point when data collection will stop and the analysis of the study will occur. |
El final del estudio para un participante determinado será cuando el participante interrumpa permanentemente el tratamiento del estudio con alpelisib y se completen todos los procedimientos de fin del estudio (incluido el seguimiento de seguridad de 30 días). La finalización global del estudio se define como el momento en el que se detenga la recopilación de datos y se realice el análisis del estudio. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 6 |