E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of adenovirus infections in high-risk (i.e., T cell depleted) pediatric allogeneic hematopoietic cell transplant recipients |
trattamento delle infezioni da Adenovirus in riceventi pediatrici di trapianto allogenico di cellule ematopoietiche ad alto rischio (ovvero con deplezione dei linfociti T) |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of adenovirus infection in children after a bone marrow transplant |
Trattamento delle infezioni da Adenovirus in bambini dopo un trapianto di midollo osseo |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10060931 |
E.1.2 | Term | Adenovirus infection |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
The primary objective of the study is to compare the safety, overall tolerability, and virologic response of BCV vs. SoC for the treatment of AdV infection in high-risk pediatric allogeneic HCT recipients. |
Questo studio è disegnato per valutare la sicurezza, la tollerabilità complessiva e l'attività antivirale della terapia BCV “a breve ciclo” rispetto all'attuale standard di cura (SoC), per il trattamento delle infezioni da Adenovirus (AdV) in riceventi pediatrici di trapianto allogenico di cellule ematopoietiche (HCT) ad alto rischio. |
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E.2.2 | Secondary objectives of the trial |
• To assess the incidence of and time to all-cause, non-relapse, and AdV-associated mortality in pediatric subjects treated with BCV vs. SoC • To assess the correlation between virologic response and clinical outcome • To describe the incidence of and time to virologic relapse in subjects who have previously achieved undetectable AdV viremia |
• Valutare l'incidenza della e il tempo alla mortalità per qualsiasi causa, non legata a recidiva e associata ad AdV in soggetti pediatrici trattati con BCV vs. SoC • Valutare la correlazione tra la risposta virologica e l'esito clinico • Descrivere l'incidenza e il tempo alla recidiva virologica nei soggetti che hanno precedentemente raggiunto la viremia da AdV non rilevabile
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Aged at least 2 months and less than 18-years-old on Day 1. • Have received a T cell-depleted allogeneic HCT within the previous 100 days. • First detectable AdV DNA plasma viremia since the qualifying transplant occurred within 21 days prior to Day 1. • AdV DNA plasma viremia ≥ 1000 copies/mL and rising, defined as two consecutive results ≥ 1000 copies/mL from the designated central virology laboratory, with the second result being greater than the first. |
• E.4 Criteri di esclusione principali(elencare i più importanti): Qualsiasi diarrea di Grado 4 CTCAE ( (cioè conseguenze potenzialmente letali con indicazione di intervento urgente) nei 7 giorni precedenti il Giorno 1 • Qualsiasi diarrea di Grado 2 o 3 CTCAE (cioè aumento di ≥ 4 evacuazioni al giorno rispetto al baseline), a meno che attribuita ad AdV, nei 7 giorni precedenti il Giorno 1 • Malattia del trapianto contro l'ospite (GVHD, graft versus host disease) acuta della cute di Stadio 4 NIH (cioè eritroderma generalizzato con formazione di bolle) nei 7 giorni precedenti il Giorno 1 • GVHD acuta del fegato di Stadio 2 NIH o superiore (cioè bilirubina > 3 mg/dl [SI: > 51 μmol/l]) nei 7 giorni precedenti il Giorno 1 • GVHD acuta dell'intestino di Stadio 2 NIH o superiore (cioè diarrea > 556 ml/m2/giorno, o dolore addominale grave con o senza ileo) nei 7 giorni precedenti il Giorno 1 • Malignità attiva (con l'eccezione del cancro della pelle non-melanoma), compresa la ricaduta o la progressione della malattia per la quale il trapianto di qualificazione è stato effettuato • PT-INR> 2x al limite superiore del valore di riferimento normale (ULN) in assenza di anticoagulanti nei 7 giorni precedenti il primo giorno. • Necessità di ventilazione meccanica nei 7 giorni precedenti il Giorno 1, o erogazione sostenuta di ossigeno > 24 ore nei 7 giorni precedenti il Giorno 1 o qualsiasi necessità di ossigeno nelle 48 ore precedenti il Giorno 1 • Necessità di ventilazione meccanica nei 7 giorni precedenti il Giorno 1, o erogazione sostenuta di ossigeno > 24 ore nei 7 giorni precedenti il Giorno 1 o qualsiasi necessità di ossigeno nelle 48 ore precedenti il Giorno 1 • Necessità di ventilazione meccanica nei 7 giorni precedenti il Giorno 1, o erogazione sostenuta di ossigeno > 24 ore nei 7 giorni precedenti il Giorno 1 o qualsiasi necessità di ossigeno nelle 48 ore precedenti il Giorno 1 • Necessità di ventilazione meccanica nei 7 giorni precedenti il Giorno 1, o erogazione sostenuta di ossigeno > 24 ore nei 7 giorni precedenti il Giorno 1 o qualsiasi necessità di ossigeno nelle 48 ore precedenti il Giorno 1 • Clearance stimata della creatinina < 30 ml/min o uso di terapia sostitutiva renale (es. emodialisi, terapia sostitutiva renale continua, dialisi peritoneale) nei 7 giorni precedenti il Giorno 1 • ALT > 5x ULN, AST > 5x ULN, bilirubina totale > 3 mg/dl (SI: > 51 μmol/l) nei 7 giorni precedenti il Giorno 1 • Infezione da virus dell'immunodeficienza umana (HIV) come rilevato attraverso qualsiasi metodo di laboratorio (ad esempio saggio di immunoassorbimento legato all'enzima, Western Blot, RNA PCR). [Nota: test per confermare l'assenza di infezione HIV è richiesta allo screening a meno che il test non sia stato eseguito dal laboratorio locale entro 6 mesi prima dello screening • Soggetti di sesso femminile incinte o in allattamento o che intendono rimanere incinte 90 giorni dopo l'ultima dose di BCV • Ricevere o sapere di dover prendere i farmaci vietati in questo protocollo (vedere la sezione 8.6.1). • Ipersensibilità (esclusa disfunzione renale o disturbi agli occhi) a CDV o BCV o suoi eccipienti. • • Partecipazione a un'altra sperimentazione clinica interventistica salvo prima sia stato approvato da Chimerix Medical Monitor (o designato) (vedi Sezione 8.6.1.3). • Qualsiasi terapia cellulare anti-AdV ricevuta nelle 6 settimane precedenti il Giorno 1 o vaccino anti-AdV precedentemente ricevuto in qualsiasi momento
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E.4 | Principal exclusion criteria |
• Any CTCAE Grade 4 diarrhea (i.e., life-threatening consequences with urgent intervention indicated) within 7 days prior to Day 1. • Any CTCAE Grade 2 or 3 diarrhea (i.e., increase of ≥ 4 stools per day over baseline), unless attributed to AdV, within 7 days prior to Day 1. • NIH Stage 4 acute GVHD of the skin (i.e., generalized erythroderma with bullous formation) within 7 days prior to Day 1. • NIH Stage 2 or higher acute GVHD of the liver (i.e., bilirubin > 3 mg/dL [SI: > 51 μmol/L]) within 7 days prior to Day 1. • NIH Stage 2 or higher acute GVHD of the gut (i.e., diarrhea > 556 mL/m2/day, or severe abdominal pain with or without ileus) within 7 days prior to Day 1. • Active malignancy (with the exception of non-melanoma skin cancer), including relapse or progression of the underlying disease for which qualifying transplant was performed. • Use of vasopressors within 7 days prior to Day 1. • PT-INR > 2x upper limit of normal reference range (ULN) in the absence of anticoagulation within 7 days prior to Day 1. • Requirement for mechanical ventilation within 7 days prior to Day 1, or sustained oxygen delivery for > 24 hours within 7 days prior to Day 1, or any oxygen requirement within 48 hours prior to Day 1. • Estimated creatinine clearance < 30 mL/min or use of renal replacement therapy (e.g., hemodialysis, continuous renal replacement therapy, peritoneal dialysis) within 7 days prior to Day 1. • ALT > 5x ULN, AST > 5x ULN, or total bilirubin > 3 mg/dL [SI: > 51 μmol/L] within 7 days prior to Day 1. • Human immunodeficiency virus (HIV) infection as detected through any laboratory method (e.g., enzyme-linked immunosorbent assay, Western Blot, RNA PCR). [Note: Testing to confirm the absence of HIV infection is required at screening unless testing was performed by the local laboratory within 6 months prior to screening.]. • Females who are pregnant or breastfeeding or planning to become pregnant within 90 days after their last anticipated dose of BCV. • Receiving or anticipated to receive medications prohibited in this protocol (see Section 8.6.1). • Hypersensitivity (not including renal dysfunction or eye disorder) to CDV or to BCV or its formulation excipients. • Participation in another interventional clinical trial unless prior approval has been received from the Chimerix Medical Monitor (or designee) (see Section 8.6.1.3). • Received any cell-based anti-AdV therapy within 6 weeks prior to Day 1 or previously received an anti-AdV vaccine at any time. |
E.4.EN Principal exclusion criteria (up to 4000 characters)(Criteri di esclusione principali, in inglese): • Any CTCAE Grade 4 diarrhea (i.e., life-threatening consequences with urgent intervention indicated) within 7 days prior to Day 1. • Any CTCAE Grade 2 or 3 diarrhea (i.e., increase of ≥ 4 stools per day over baseline), unless attributed to AdV, within 7 days prior to Day 1. • NIH Stage 4 acute GVHD of the skin (i.e., generalized erythroderma with bullous formation) within 7 days prior to Day 1. • NIH Stage 2 or higher acute GVHD of the liver (i.e., bilirubin > 3 mg/dL [SI: > 51 μmol/L]) within 7 days prior to Day 1. • NIH Stage 2 or higher acute GVHD of the gut (i.e., diarrhea > 556 mL/m2/day, or severe abdominal pain with or without ileus) within 7 days prior to Day 1. • Active malignancy (with the exception of non-melanoma skin cancer), including relapse or progression of the underlying disease for which qualifying transplant was performed. • Use of vasopressors within 7 days prior to Day 1. Uso di vasopressori nei 7 giorni precedenti il day 1 • PT-INR > 2x upper limit of normal reference range (ULN) in the absence of anticoagulation within 7 days prior to Day 1. • Requirement for mechanical ventilation within 7 days prior to Day 1, or sustained oxygen delivery for > 24 hours within 7 days prior to Day 1, or any oxygen requirement within 48 hours prior to Day 1. • Estimated creatinine clearance < 30 mL/min or use of renal replacement therapy (e.g., hemodialysis, continuous renal replacement therapy, peritoneal dialysis) within 7 days prior to Day 1. • ALT > 5x ULN, AST > 5x ULN, or total bilirubin > 3 mg/dL [SI: > 51 μmol/L] within 7 days prior to Day 1. • Human immunodeficiency virus (HIV) infection as detected through any laboratory method (e.g., enzyme-linked immunosorbent assay, Western Blot, RNA PCR). [Note: Testing to confirm the absence of HIV infection is required at screening unless testing was performed by the local laboratory within 6 months prior to screening.]. • Females who are pregnant or breastfeeding or planning to become pregnant within 90 days after their last anticipated dose of BCV. • Receiving or anticipated to receive medications prohibited in this protocol (see Section 8.6.1). • Hypersensitivity (not including renal dysfunction or eye disorder) to CDV or to BCV or its formulation excipients. • Participation in another interventional clinical trial unless prior approval has been received from the Chimerix Medical Monitor (or designee) (see Section 8.6.1.3). • Received any cell-based anti-AdV therapy within 6 weeks prior to Day 1 or previously received an anti-AdV vaccine at any time.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the time-averaged area under the concentration-time curve (AAUC) for AdV viremia (log10 copies/mL) through Week 16 post-randomization. |
L'endpoint primario di efficacia per questo studio è l'area tempo-mediata sotto la curva concentrazione tempo (AAUC) per la viremia da AdV (log10 copie/ml) dalla randomizzazione fino alla Settimana 16 post-randomizzazione |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 16 post-randomization. |
Settimana 16 post-randomizzazione |
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E.5.2 | Secondary end point(s) |
• Time to all-cause mortality. • Incidence of and time to all-cause mortality. • Incidence of and time to non-relapse mortality. • Incidence of and time to AdV-associated mortality. • Proportion of subjects with ≥ 2-log10 decline from baseline or undetectable AdV viremia at Weeks 2, 4, 6, 12 and 16. |
• Tempo alla mortalità per qualsiasi causa • Incidenza e tempo alla mortalità per qualsiasi causa • Incidenza e tempo alla mortalità non legata alla recidiva • Incidenza e tempo alla mortalità associata ad AdV • Percentuale di soggetti con calo pari a ≥ 2-log10 dal baseline o viremia da AdV non rilevabile alle Settimane 2, 4, 6, 12 e 16
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy Endpoints: until Week 16 Safety Endpoints: until Week 36
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Endpoints Efficacia : fino alla settimana 16 Endpoints di Sicurezza: fino alla settimana 36
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard of Care |
Standard of Care |
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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 | 32 |
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 |
France |
Germany |
Ireland |
Italy |
Netherlands |
Spain |
United Kingdom |
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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Last Visit Last Subject |
Last Visit Last Subject |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |