E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Influenza A Infection |
Infezione da influenza A |
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E.1.1.1 | Medical condition in easily understood language |
Seasonal flu |
Influenza stagionale |
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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 | LLT |
E.1.2 | Classification code | 10022002 |
E.1.2 | Term | Influenza A virus infection |
E.1.2 | System Organ Class | 100000004862 |
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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 |
The primary objective is to evaluate superiority of pimodivir in combination with standard-of-care (SOC) treatment compared to placebo in combination with SOC treatment on Day 6, with respect to the clinical outcome on the hospital recovery scale. |
L’obiettivo primario è valutare la superiorità di pimodivir in combinazione con il trattamento standard di cura (SOC) rispetto al placebo in combinazione con il trattamento SOC il Giorno 6, in riferimento all’esito clinico sulla scala di recupero ospedaliero. |
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E.2.2 | Secondary objectives of the trial |
Compare pimodivir (Pi) in combination with SOC treatment (tmt) to placebo in combination with SOC tmt (Pi+SOC_Pl+SOC) re.: * Safety, tolerability * All-cause mortality * Incidence, duration of antibiotic tmt * No. of subjects needing extended tmt, requiring re-hospitalization, not hospitalized at Day 6 * Time to clin response * Time to improvement of respiratory status Evaluate superiority of Pi+SOC vs.Pl+SOC with respect to: * Length of hospital stay, time in ICU, time on mechanical ventilation, time to return to daily activities * Clinical outcome on hospital recovery scale * Incidence of complications associated with influenza after start of study tmt * Time to viral negativity a. viral load over time by qRT-PCR and viral culture * PK of Pi; PK/PD relationships of Pi Investigate: * Acceptability (taste, swallowability) of Pi formulation in adolescents * Emergence of viral resistance against Pi * Virologic response by baseline resistance to Pi/other antivirals in SOC |
Valutare pimodivir (Pi) in combinazione con il trattamento SOC (tmt) rispetto al placebo in combinazione con il trattamento SOC (Pi+SOC_Pi+SOC): *sicurezza, tollerabilità *mortalità per qualsiasi causa *incidenza e la durata del trattamento antibiotico *numero di soggetti che necessitano di un trattamento esteso tmt, di un nuovo ricovero, non ricoverati il Giorno 6 *tempo alla risposta clinica *tempo al miglioramento dello stato respiratorio Valutare la superiorità di Pi+SOC vs PI+SOC in riferimento ai seguenti parametri: *durata della degenza ospedaliera, intervallo di tempo trascorso in una unità di terapia intensiva (UTI), durata della terapia con ventilazione meccanica, tempo necessario per il ritorno alle attività quotidiane *esito clinico sulla scala di ricovero ospedaliero *all’incidenza di complicazioni associate all’influenza dopo l’inizio del trattamento dello studio *tempo alla negatività virale;carica virale nel tempo mediante qRT-PCR e coltura virale * PK di Pi; relazionPK |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Taste and Swallowability in adolescents (integrated part of the protocol) |
Gusto e deglutibilità negli adolescenti (parte integrata del protocollo) |
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E.3 | Principal inclusion criteria |
• Male or female, 13 to 85 years of age, inclusive. Note: Adolescent subjects (13-17 years) will be enrolled in selected countries and study sites consistent with local regulations. • Tested positive for influenza A infection after the onset of symptoms using a polymerase chain reaction (PCR)-based molecular diagnostic assay. • Requires hospitalization to treat influenza infection and/or to treat complications of influenza infection (eg, radiological signs of lower respiratory tract disease, septic shock, central nervous system [CNS] involvement, myositis, rhabdomyolysis, acute exacerbation of chronic kidney disease, severe dehydration, myocarditis, pericarditis, ischemic heart disease, exacerbation of underlying chronic pulmonary disease, including asthma, chronic obstructive pulmonary disease [COPD], decompensation of previously controlled diabetes mellitus), including subjects admitted to the intensive care unit (ICU). Note: For the purpose of the protocol, subjects admitted under “observation” status with an anticipated length of stay beyond 24 hours are eligible for enrollment. • Enrollment and initiation of study drug treatment ≤96 hours after onset of influenza symptoms. • Having an SpO2 <94% on room air. Subjects with known pre influenza SpO2 <94% must have an SpO2 decline ≥3% from pre-influenza SpO2. • Having a screening/baseline NEWS of ≥4.
Treatment Extension Criteria - Subjects will be given the option for treatment extension in case all of the following conditions are met: • The subject completed the 5-day treatment period. • The subject is still hospitalized. • Subject has an ongoing respiratory deficiency as evidenced by having an SpO2 <94% on room air, or in case of pre-existing chronic hypoxia (eg, due to COPD), the current blood oxygen saturation on room air is lower than pre-influenza infection levels by at least 2%. • The subject is expected to derive clinical benefit from extending the treatment period, in the opinion of the investigator. • The investigator agrees to extend treatment with the same SOC. If the SOC contained no influenza antiviral during the first treatment period, no new influenza antiviral can be started in the treatment extension as part of the SOC. |
-Soggetti ambosessi, 13 e 85 anni compresi. Nota: i soggetti adolescenti (13-17 anni) saranno arruolati in Paesi e centri di studio selezionati conformemente alle normative locali. -Positività all’infezione da influenza A dopo la comparsa dei sintomi determinata mediante un saggio diagnostico molecolare basato sulla reazione a catena della polimerasi (PCR). -Necessità di ricovero per il trattamento dell’infezione da influenza e/o di complicazioni della stessa (ad es. segni radiologici di malattia delle vie respiratorie inferiori, shock settico, coinvolgimento del sistema nervoso centrale [SNC], miosite, rabdomiolisi, esacerbazione acuta della nefropatia cronica, grave disidratazione, miocardite, pericardite, cardiopatia ischemica, esacerbazione di una pneumopatia cronica sottostante, compresi asma, broncopneumopatia cronica ostruttiva [BPCO], scompenso di diabete mellito precedentemente controllato), che comprende i soggetti ricoverati nell’unità di terapia intensiva (UTI). Nota: ai fini del protocollo, i soggetti ricoverati in stato di “osservazione” con una durata prevista della degenza oltre 24 ore sono idonei all’arruolamento. -Arruolamento e inizio del trattamento con il farmaco dello studio ≤96 ore dopo la comparsa dei sintomi influenzali. -SpO2 <94% in aria ambiente. I soggetti con SpO2 pre-influenza <94% nota devono mostrare una riduzione nella SpO2 ≥3% rispetto alla SpO2 pre-influenza. -Punteggio NEWS allo screening/al basale ≥4. |
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E.4 | Principal exclusion criteria |
• Received more than 3 doses of influenza antiviral medication (eg, oseltamivir [OST] or zanamivir), or any dose of ribavirin within 2 weeks, prior to first study drug intake. Received intravenous (IV) peramivir more than one day prior to screening.
• Unwilling to undergo regular nasal mid-turbinate (MT) swabs or has any physical abnormality which limits the ability to collect regular nasal MT specimens.
• Unstable angina pectoris or myocardial infarction within 30 days prior to screening (inclusive).
• Presence of clinically significant heart arrhythmias, uncontrolled, unstable atrial arrhythmia, or sustained ventricular arrhythmia, or risk factors for Torsade de Pointes syndrome.
• Chronic hepatitis C infection undergoing antiviral therapy.
• Severely immunocompromised in the opinion of the investigator (eg, cluster of differentiation 4+ [CD4+] count <200 cells/mm3, absolute neutrophil count <750/mm3, first course of chemotherapy completed within 2 weeks prior to screening, history of stem cell transplant within 1 year prior to screening, any history of a lung transplant). |
-Precedente trattamento con più di 3 dosi di farmaco antivirale antinfluenzale (ad es. oseltamivir [OST] o zanamivir) o qualsiasi dose di ribavirina nelle 2 settimane precedenti la prima assunzione del farmaco dello studio. Trattamento endovenoso (EV) con peramivir risalente a oltre un giorno prima dello screening. -Riluttanza a sottoporsi al regolare prelievo di tamponi nasali del turbinato medio (TM) o presenza di una qualsiasi anomalia fisica che limiti la possibilità di raccogliere regolarmente campioni nasali di TM. -Angina pectoris instabile o infarto miocardico nei 30 giorni precedenti lo screening (compreso). -Presenza di aritmie cardiache clinicamente significative, aritmia atriale instabile non controllata o aritmia ventricolare sostenuta o fattori di rischio per la sindrome da torsione di punta. -Infezione cronica da epatite C sottoposta a terapia antivirale. -Immunocompromissione grave secondo il parere dello sperimentatore (ad es. conta di cellule positive per il cluster di differenziazione 4+ [CD4+] <200 cellule/mm3, conta neutrofilica assoluta <750/mm3, primo ciclo di chemioterapia completato nelle 2 settimane precedenti lo screening, anamnesi di trapianto di cellule staminali entro 1 anno prima dello screening, qualsiasi anamnesi di trapianto di polmone). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the hospital recovery scale as assessed on Day 6. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The hospital recovery scale assesses a subject’s clinical status and will be assessed as the subject’s condition on Day 6 as the primary endpoint. |
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E.5.2 | Secondary end point(s) |
1. Safety and tolerability based on assessment of AEs, clinical laboratory assessments, 12-lead electrocardiograms (ECGs), vital signs, and peripheral capillary oxygen saturation.
2. Length of hospital stay.
3. Length of time in the ICU.
4. Length of time on mechanical ventilation.
5. The hospital recovery scale as assessed each separate day from Days 4 to 14 (excluding the primary time point).
6. Time to return to daily activities.
7. Incidence of complications associated with influenza after the start of study treatment.
8. All-cause mortality.
9. Incidence and duration of antibiotic treatment.
10. The number (proportion) of subjects needing extended treatment.
11. The number (proportion) of subjects requiring re-hospitalization.
12. The number (proportion) of subjects not hospitalized at Day 6.
13. Time to clinical response.
14. Time to respiratory response.
15. PK parameters of pimodivir (ie, plasma concentration just prior to the beginning or at the end of a dosing interval [Ctrough], Cmax, tmax, and AUC12h), as determined by population PK analysis.
16. PK/pharmacodynamic (PD) analyses.
17. The acceptability of the pimodivir formulation in adolescents, as measured by a taste and swallowability questionnaire.
18. Time to viral negativity by qRT-PCR and viral culture.
19. Viral load over time by qRT-PCR and viral culture.
20. The emergence of viral resistance against pimodivir detected by genotyping and/or phenotyping.
21. Virologic response by baseline viral resistance to pimodivir/other antivirals in the SOC. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.-4., 6.-9. Day 33
5. Day 14
10.-16. Final analysis
17. Day 5
18.-20 Day19
21. Day 0/1 |
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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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
- Acceptability of pimodivir formulation in adolescents
- Emergence of viral resistance against pimodivir
- Virologic response to pimodivir/other antivirals in the SOC
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- Accettabilità della formulazione di pimodivir negli adolescenti - Emergenza della resistenza virale contro pimodivir - Risposta virologica a pimodivir / altri antivirali nella SOC |
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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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Progetto aggiuntivo al SoC (scelta dello sperimentatore: terapia antivirale e / o terapia di support |
Add-on design to SoC (investigator's choice: antiviral therapy and/or supportive care) |
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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 | 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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 105 |
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 | Information not present in EudraCT |
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 |
Belgium |
Brazil |
Bulgaria |
Chile |
Czech Republic |
France |
Germany |
Hungary |
India |
Israel |
Italy |
Korea, Republic of |
Lithuania |
Malaysia |
Mexico |
Netherlands |
New Zealand |
Peru |
Poland |
Romania |
Russian Federation |
Singapore |
Slovakia |
South Africa |
Spain |
Sweden |
Taiwan |
Thailand |
Turkey |
Ukraine |
United States |
Vietnam |
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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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LVLS |
Ultima visita dell'ultimo paziente |
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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 | 4 |
E.8.9.1 | In the Member State concerned days | 11 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 11 |