E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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. |
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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:
* Tmt time in hospital, 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 |
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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) |
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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 or other rapid 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.
• Being on invasive mechanical ventilation or having an SpO2 <94% on room air during screening. Subjects with known pre influenza SpO2 <94% must have an SpO2 decline ≥3% from pre-influenza SpO2.
• Having a screening/baseline National Early Warning Score (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.
• The subject is on invasive mechanical ventilation or has or has an ongoing respiratory deficiency as evidenced by having an SpO2 <94% on room air, or in case of known pre-influenza SPO<94% 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 3%.
• 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 influenza antiviral can be started in the treatment extension as part of the SOC. |
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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.
• Known severe hepatic impairment (Child Pugh C cirrhosis) or chronic hepatitis C infection undergoing hepatitis C antiviral therapy.
• Severely immunocompromised in the opinion of the investigator (eg, known 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). |
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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 adverse events (AEs),
clinical laboratory assessments, 12-lead electrocardiograms (ECGs), vital
signs, and peripheral capillary oxygen saturation.
2. Time from start of study drug to hospital discharge and total length of
hospital stay.
3. Time from ICU admission to ICU discharge and total time in ICU.
4. Time from start to end of mechanical ventilation and total time on
mechanical ventilation.
5. The hospital recovery scale as assessed each separate day from Days
2 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. The acceptability of the pimodivir formulation in adolescents, as
measured by a taste and swallowability questionnaire.
17. Time to viral negativity by qRT-PCR and viral culture.
18. Viral load over time by qRT-PCR and viral culture.
19. The emergence of viral resistance against pimodivir detected by
genotyping and/or phenotyping. |
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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.-15. Final analysis
16. Day 5
17.-19. Day19
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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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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 |
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 | 2 |
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 | 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 |
Austria |
Belgium |
Brazil |
Bulgaria |
Chile |
Czech Republic |
France |
Germany |
Hungary |
India |
Israel |
Italy |
Korea, Republic of |
Latvia |
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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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 | 8 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 11 |