E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Influenza A infection in hospitalized patients who need supplemental oxygen |
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E.1.1.1 | Medical condition in easily understood language |
Flu infection in hospitalized patients who need breathing assistance using oxygen-delivery devices |
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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 | 20.0 |
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 | 100000015765 |
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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 efficacy objective is to evaluate the effect of 2 dose levels of VIS410 + oseltamivir on the time to normalization of respiratory function compared to oseltamivir alone.
The primary safety objective is to evaluate safety and tolerability of 2 dose levels of a single intravenous (IV) dose of VIS410 when administered in combination with oseltamivir in hospitalized subjects with influenza A infection |
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E.2.2 | Secondary objectives of the trial |
• Evaluate the effect of VIS410 + oseltamivir vs oseltamivir alone on the following endpoints:
Viral load in upper respiratory samples
Time to clinical response
Time to cessation of ventilator support
Time to resumption of normal activities
All-cause and attributable 14- and 28-day mortality
Healthcare resource utilization
Time to alleviation of clinical symptoms of influenza in subset of subjects able to complete the FluPRO Questionnaire at baseline and post-dose
Proportion of subjects with new documented bacterial pneumonia/superinfection
Proportion of subjects with influenza-related complications
• Pharmacokinetics of VIS410 in serum
• Immunogenicity of VIS410
• Emergence of resistance to VIS410 and oseltamivir |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects meeting all of the following criteria are eligible to participate in this study:
1. Male and female subjects aged ≥ 18 years. For a country where the legal age of consent is >18 years old, the country requirements should be followed.
2. Test positive for influenza A by rapid antigen test or with another commercially available test on an adequate nasopharyngeal specimen in accordance with the manufacturer's instructions, or an acceptable local test including, PCR, FIA, or ELISA
3. Onset of influenza symptoms no more than 5 days before VIS410/placebo infusion; symptoms may include cough, dyspnea, sore throat, fever, myalgias, headache, nasal symptoms (rhinorrhea, congestion), fatigue, diarrhea, anorexia, nausea, and vomiting.
4. Requirement for oxygen support including any positive pressure ventilation (PPV).
5. Women of childbearing potential must have a negative pregnancy test within 2 days prior to VIS410/placebo infusion.
6. Women should fulfill one of the following criteria:
a. Post-menopausal; either amenorrhea ≥ 12 months or follicle stimulating hormone > 40 mIU/mL as documented in their medical history
b. Surgically sterile; hysterectomy, bilateral oophorectomy, or tubal ligation
c. Women of childbearing potential participating in heterosexual relations must be willing to use adequate contraception from screening until 60 days post VIS410/placebo infusion (see Section 6.2).
7. Non-vasectomized (or vasectomized less than 6 months prior to dosing) male subjects who have a female partner of childbearing potential must use an effective birth control method (see Section 6.2) when having heterosexual intercourse, from screening until 60 days post VIS410/placebo infusion.
8. Subject is able and willing to comply with study procedures, as per protocol.
9. Subject, or a legally authorized representative is able to understand the purpose and risks of the study and willing to give voluntary written informed consent. |
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E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria are excluded from participation in this study:
1. Known or suspected intolerance or hypersensitivity to VIS410, oseltamivir, pretreatment medications (diphenhydramine, or to both ibuprofen and acetylsalicylic acid [ASA]), or closely related compounds (eg, other monoclonal antibodies).
2. Subjects who have received VIS410 in the past.
3. Subjects who have a history of receiving monoclonal antibody products within 3 months prior to VIS410/placebo dosing or planned administration of another monoclonal antibody during the study period.
4. Subjects who have taken more than 6 doses of an approved antiviral therapy for influenza within the prior 96 hours (eg, oral oseltamivir, inhaled zanamivir, IV peramivir, or oral ribavirin) between onset of symptoms and VIS410/placebo dosing.
5. Subjects with known co-infection with influenza B or other viral respiratory infections (eg, respiratory syncytial virus [RSV], parainfluenza viruses, respiratory adenoviruses).
6. Subjects with lung transplant or history of severe chronic lung disease, including cystic fibrosis or any condition requiring home oxygen therapy.
7. Subjects on extracorporeal membrane oxygenation at time of randomization.
8. Subjects with end-stage renal disease (ESRD) who are not undergoing hemodialysis.
9. Subjects with active graft-vs-host disease, hematopoietic stem cell transplant within the previous 90 days, or human immunodeficiency virus infection with a CD4 cell count of less than 200 per cubic millimeter.
10. High probability of mortality within 48 hours of randomization as determined by the Investigator.
11. Women who are pregnant, breast-feeding, or considering to become pregnant.
12. Subjects in whom nasopharyngeal swabbing is not possible.
13. Subjects weighing less than 45 kg.
14. Enrollment in any other investigational drug or device study, any disease or vaccine study within 30 days prior to Day 1 or within 5 half-lives of the investigational compound, whichever is longer.
15. Presence of any preexisting illness that, in the opinion of the Investigator, would place the subject at an unreasonably increased risk through participation in this study.
16. Subjects unable to comply with study protocol procedures and study visit schedules for whatever reason.
17. Known or suspected alcohol or drug abuse, that is, abuse of a level that would compromise the safety or cooperation of the subject in the opinion of the Investigator. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the time to cessation of oxygen (O2) support resulting in stable oxygen saturation (SpO2) by pulse oximetry. Stable SpO2 is defined as two consecutive SpO2 values of > 92% on room air that are at least 8 hours apart.
The primary safety endpoint is the proportion of subjects with AEs and SAEs following administration of VIS410. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The endpoints can be evaluated by hospital staff at any time while the patient is hospitalized or during patient visit in case of a discharged patient. |
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E.5.2 | Secondary end point(s) |
The difference between VIS410 + oseltamivir and oseltamivir alone treatment groups in the following endpoints:
• Peak viral load, viral AUC, duration of viral shedding, and time to resolution of viral load from nasopharyngeal swabs by TCID50 and qRT-PCR
• Time to clinical response defined as resolution of at least 4 of 5 vital signs
Afebrile with core temperature ≤ 37.8°C, without use of antipyretics (oral < 37.2°C)
Oxygen saturation ≥ 95% on room air without support or a return to pre-infection status, if pre-infection status was < 95%
Pulse rate ≤ 100/min
Systolic blood pressure ≥ 90 mm/Hg, without vasopressor use
Respiratory rate ≤ 24 beats per minute
• Total number of days on ventilation
• Number of days to resumption of usual activities
• All-cause and attributable mortality rates at Day 14 and 28
• Total number of days in hospital and/or intensive care unit (ICU) from admission to discharge and rate of rehospitalization due to influenza A relapse/complication
• The incidence, severity, and duration of signs and symptoms of influenza-like illness as assessed by the FluPRO Questionnaire (see Appendix 14.1)
• The percentage of subjects with new bacterial pneumonia/superinfection
• The percentage of subjects with influenza-related complications
• VIS410 population pharmacokinetic (PK) parameters in serum
• Titer of anti-VIS410 antibody positive samples
• Genotypic and/or phenotypic assessment to determine the emergence of VIS410 and oseltamivir-resistant viruses |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The endpoints can be evaluated by hospital staff at any time while the patient is hospitalized or during patient visit in case of a discharged patient. |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 48 |
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 |
Belarus |
Belgium |
Bulgaria |
Canada |
Estonia |
France |
Georgia |
Israel |
Italy |
Korea, Republic of |
Latvia |
Lithuania |
Malaysia |
Mexico |
New Zealand |
Peru |
Romania |
Russian Federation |
Serbia |
Singapore |
South Africa |
Spain |
Thailand |
Turkey |
Ukraine |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 31 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 31 |