Cough, Fever, Headache, Nasal Congestion, Seasonal Influenza, Sore Throat
Conditions
Keywords
Influenza, Hospitalized, Antiviral, Flu
Brief summary
A Phase 3, multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of peramivir administered intravenously in addition to standard of care compared to standard of care alone in adults and adolescents who are hospitalized due to serious influenza.
Interventions
DRUGPeramivir+SOC
* Adults (≥ 18 years): Peramivir (BCX-1812) 600 mg, administered intravenously, once daily (every 24 hrs) for 5 days (5 doses) in addition to institution's standard of care. * Adolescents (12-17 years): Peramivir (BCX-1812) 10 mg/kg (not to exceed a maximum dose of 600 mg), administered intravenously, once daily (every 24 hrs) for 5 days (5 doses) in addition to institution's standard of care.
DRUGPlacebo+SOC
Placebo Peramivir (BCX1812) administered intravenously, once daily (every 24 hrs) for 5 days (5 doses) in addition to institution's standard of care.
Sponsors
Department of Health and Human Services
BioCryst Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥12 years of age, male or female. * Able to provide informed consent, or for whom consent may be provided by guardian, unless informed consent provided by a guardian or a legally authorized representative is not consistent with applicable local or ethical concerns, procedures, directives and/or guidelines. * Subject must have at least one of the following clinical presentations at Screening: 1. Oral temperature ≥ 38.0 °C (≥100.4 °F), ≥38.6°C (≥101.4 °F) tympanic or rectal OR 2. Oxygen saturation \<92%, OR 3. Two out of the following three vital signs: Respiration rate \>24/minute, Heart rate \>100/minute, Systolic BP \<90 mmHg * Presence of at least one respiratory symptom (cough, sore throat, or nasal congestion) of any severity (mild, moderate, or severe). * Presence of at least one constitutional symptom (headache, myalgia, feverishness, or fatigue) of any severity (mild, moderate, or severe). * Onset of illness no more than 72 hours before presentation. Note: Time of onset of illness is defined as the earlier of either (1) the time when the temperature was first measured as elevated, OR (2) the time when the subject experienced the presence of at least one respiratory symptom AND the presence of at least one constitutional symptom. * Either: Severity of illness that, in the Investigator's judgment, justifies hospitalization of the subject for supportive care. OR Presence of one or more of the following factors: Age ≥60 years. Presence of chronic obstructive pulmonary disease (COPD) or other chronic lung disease requiring daily pharmacotherapy. Current history of congestive heart failure or angina. Presence of diabetes mellitus, clinically stable or unstable. Transcutaneous oxygen saturation \<94% without supplemental oxygen for at least 5 minutes, or a medically significant decrease in oxygen saturation from an established baseline value (an investigative site at altitude \>2000 ft above sea level will utilize different criteria for oxygen saturation). History of chronic renal impairment not requiring peritoneal dialysis. Serum creatinine \> 2.0 mg/dL or \> 177 μmol/L. * Diagnosis of Influenza by satisfying one of the following: 1. Clinical Influenza with Positive Diagnostic Test. Subjects who have a positive rapid antigen test (RAT) for influenza A and/or influenza B (using a Sponsor-approved test kit), or positive test (using other methodology) for influenza A and/or B virus antigen or RNA performed in a clinical laboratory at the screening/enrollment evaluation are eligible for enrollment. OR 2. Clinical Influenza with Negative Rapid Antigen Test (RAT). Subjects with a negative RAT test may be enrolled once the site has been approved by the Sponsor to enroll such subjects, based on documentation of an outbreak of influenza in the community. An influenza outbreak may be documented in the catchment area of the hospital via one of the following methods: 1) local confirmation of influenza A or B infection in the current influenza season by a) the institution's local laboratory, or b) the local public health system, or c) the national public health system, or d) a laboratory of a recognized multinational influenza surveillance scheme such as the European Influenza Surveillance Network (EISN); 2) prior enrollment of a RAT positive subject into this study at the same institution in the current influenza season.
Exclusion criteria
* Subjects who have been hospitalized for greater than 24 hours (not including time spent in the Emergency Department). * Treatment with any dose(s) of rimantadine, amantadine, ribavirin, zanamivir, or oseltamivir in the previous 7 days. * Blood platelet count of \< 20 x 109/L at the time of the screening evaluation. * Serum bilirubin \> 6 mg/dL or \> 105 μmol/L at time of screening evaluation. * Serum ALT or AST \> 5 times the upper limit of normal at time of screening evaluation. * Congestive heart failure of NYHA Class III or Class IV functional status. * Serum creatinine \> 5.0 mg/dL or \> 500 μmol/L at time of screening evaluation. * Subjects who require peritoneal dialysis. * Altered neurologic status as defined by a Glasgow Coma Score of ≤ 9, unless medically induced. * Females who are pregnant (positive urine or serum pregnancy test at screening evaluation) or breastfeeding. * Actively undergoing systemic chemotherapy or radiotherapy treatment for a malignancy. Subjects who have completed treatment 30 days prior to enrollment are not excluded. Hormone treatment for cancer is also not excluded. * Prior hematopoietic stem cell transplantation or solid organ transplant during the previous 4 months. * HIV infection with a known CD4 count \< 200 cells/mm3 unless on a stable highly active antiretroviral therapy (HAART) for at least 6 months. * Presence of a pre-existing chronic infection that is undergoing or requiring medical therapy (eg, tuberculosis). Subjects with chronic osteomyelitis or Hepatitis B or C not requiring treatment are not excluded. * Presence of any pre-existing illness that, in the opinion of the investigator, would place the subject at an unreasonably increased risk through participation in this study. * Previous treatment with intravenous or intramuscular peramivir. * Participation as a subject in any study of an experimental treatment for any condition within the 30 days prior to the time of the screening evaluation. * Subjects diagnosed with Cystic Fibrosis. * Subjects with confirmed clinical evidence of acute non-influenzal infection at the time of screening evaluation. * Subjects who, in the judgment of the investigator, will be unlikely to comply with the requirements of this protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Clinical Resolution (Kaplan-Meier Estimate) | 10 days | Time to clinical resolution was defined as the time in hours from initiation of study treatment until normalization of at least 4 of the 5 signs within the respective normalization criteria, maintained for at least 24-hours. Time to clinical resolution was summarized by treatment group using the method of Kaplan-Meier. For subjects who did not experience clinical resolution, values were censored at the date of their last non-missing assessment of clinical resolution during the study (whether this assessment occurred as an inpatient or as an outpatient). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change (Reduction) in Influenza Virus Titer | Baseline and 24, 48, 108 hours | The reduction in viral shedding was assessed as the change from baseline in log10 tissue culture infective dose50 (TCID50/mL) and RT-PCR and was summarized for each treatment group and study visit. |
| Time to Alleviation of Clinical Symptoms of Influenza | 10 days | Time to alleviation of clinical symptoms of influenza was measured as the time from the first dose of study drug through the time period in which all 7 symptoms of influenza (cough, sore throat, nasal congestion, myalgia \[aches and pains\], headache, feverishness, and fatigue) were absent or rated as no greater than mild for at least 24 hours. Time to alleviation of symptoms was estimated using the method of Kaplan-Meier. Subjects who did not have resolution of any individual clinical sign were censored at the time of their last non-missing assessment of that sign. |
| Time to Resolution of Fever (Kaplan-Meier Estimate) | 10 days | Time to resolution of fever was measured as the time from initiation of study treatment until resolution of fever, maintained for at least 24 hours; temperature measurements taken less than 4 hours after antipyretic use were treated as missing values. |
| Time to Resumption of Usual Activities | 10 days | Time to resumption of usual activities was determined from the visual analog scale (scale ranged from 0 to 10 where 0 indicated subject was unable to perform usual activities at all and 10 indicated subject was able to perform all usual activities fully). Time to resumption of usual activities was summarized by treatment group using the method of Kaplan-Meier. |
| Number of Subjects With ICU Admission | 10 days | The number of subjects requiring ICU admission post-randomization was summarized by treatment group. |
| Duration of All ICU Admissions (Kaplan-Meier Estimate) | 10 days | Duration of postbaseline ICU admission was defined as the total number of days in the ICU for those subjects who had a post-baseline admission to the ICU. Only days starting after the initial postbaseline admission were included. If a subject's stay in the ICU was ongoing, the duration was censored at the last study visit. Subjects who did not have a postbaseline admission had a duration of 0. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Influenza-Related Complications | 10 days | Influenza-related complications were defined as the occurrence of sinusitis, otitis, bronchitis, and pneumonia as reported on the influenza-related complications CRF. |
| Number of Subjects Requiring More Than 5 Days of Study Drug | 10 days | Subjects who had not met the protocol-defined criteria of clinical resolution on Day 5 or who had detectable virus by RT-PCR from a sample collected on Study Day 4 after dosing continued their assigned treatment for a further 5 days. |
| Survival at 14 and 28 Days After Initiation of Study Drug (Kaplan-Meier Estimate) | 28 days | Survival was calculated as the number of days from initiation of study drug until death or last contact. Estimates and 95% confidence intervals were calculated using the method of Kaplan-Meier and presented by treatment group. |
| Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | Initial (baseline or post-baseline) and up to 10 days | Initial viral sensitivity to peramivir, oseltamivir, and zanamivir was assessed over time during the study, and was presented by influenza virus subtype. Initial assessment of susceptibility may have occurred at a post-baseline visit. |
| Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | Initial (baseline or post-baseline) and up to 10 days | Viral sensitivity to peramivir, oseltamivir, and zanamivir was assessed over time during the study, and was presented as fold change from initial sensitivity by influenza virus subtype. Initial assessment of susceptibility may have occurred at a post-baseline visit. |
| Time to Hospital Discharge | 10 days | Time to hospital discharge, defined as the number of days from initiation of study treatment until the subject was discharged from the hospital, was summarized by treatment group using the method of Kaplan-Meier. Subjects who were not discharged from the hospital were censored at their last study visit. |
Countries
Argentina, Belgium, Bosnia and Herzegovina, Brazil, Bulgaria, Canada, Chile, Czechia, Germany, Hungary, India, Israel, Latvia, Lebanon, Peru, Poland, Russia, Serbia, Slovakia, South Africa, Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo+SOC Placebo Peramivir (BCX1812) administered intravenously, once daily (every 24 hrs) for 5 days (5 doses) in addition to institution's standard of care. | 137 |
| Peramivir+SOC Adults (≥ 18 years): Peramivir (BCX-1812) 600 mg, administered intravenously, once daily (every 24 hrs) for 5 days (5 doses) in addition to institution's standard of care.
Adolescents (12-17 years): Peramivir (BCX-1812) 10 mg/kg (not to exceed a maximum dose of 600 mg), administered intravenously, once daily (every 24 hrs) for 5 days (5 doses) in addition to institution's standard of care. | 268 |
| Total | 405 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Lost to Follow-up | 2 | 6 |
| Overall Study | Missing | 1 | 1 |
| Overall Study | Noncompliance; Protocol Deviations | 2 | 3 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 16 |
Baseline characteristics
| Characteristic | Total | Placebo+SOC | Peramivir+SOC |
|---|---|---|---|
| Absolute Lymphocyte Count at Baseline | 1.3 cell count STANDARD_DEVIATION 1.44 | 1.3 cell count STANDARD_DEVIATION 1.25 | 1.3 cell count STANDARD_DEVIATION 1.52 |
| Age, Continuous | 46 years | 43 years | 47 years |
| Age, Customized Adolescents 12-17 Years | 11 participants | 4 participants | 7 participants |
| Age, Customized Adults 18-24 Years | 56 participants | 23 participants | 33 participants |
| Age, Customized Adults 25-34 Years | 63 participants | 23 participants | 40 participants |
| Age, Customized Adults 35-44 Years | 65 participants | 21 participants | 44 participants |
| Age, Customized Adults 45-54 Years | 71 participants | 27 participants | 44 participants |
| Age, Customized Adults 55-64 Years | 62 participants | 17 participants | 45 participants |
| Age, Customized Adults 65-74 Years | 36 participants | 11 participants | 25 participants |
| Age, Customized Adults ≥ 75 Years | 37 participants | 9 participants | 28 participants |
| Age, Customized Children 6-11 Years | 4 participants | 2 participants | 2 participants |
| Body mass index (BMI) | 27.6 kg/m^2 | 27.7 kg/m^2 | 27.5 kg/m^2 |
| Chest X-ray at Screening Abnormal | 169 participants | 49 participants | 120 participants |
| Chest X-ray at Screening Normal | 236 participants | 88 participants | 148 participants |
| Duration of Illness ≤ 48 hours | 225 participants | 75 participants | 150 participants |
| Duration of Illness > 48 hours | 180 participants | 62 participants | 118 participants |
| ICU admission at Baseline Admitted | 50 participants | 17 participants | 33 participants |
| ICU admission at Baseline Missing | 7 participants | 3 participants | 4 participants |
| ICU admission at Baseline Not admitted | 348 participants | 117 participants | 231 participants |
| Influenza Vaccination Status Missing | 1 participants | 0 participants | 1 participants |
| Influenza Vaccination Status Not vaccinated this year | 337 participants | 111 participants | 226 participants |
| Influenza Vaccination Status Vaccinated this year | 67 participants | 26 participants | 41 participants |
| Race/Ethnicity, Customized Asian | 83 participants | 31 participants | 52 participants |
| Race/Ethnicity, Customized Black, of African Heritage or African American | 51 participants | 23 participants | 28 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Other | 29 participants | 11 participants | 18 participants |
| Race/Ethnicity, Customized White | 240 participants | 71 participants | 169 participants |
| Sex: Female, Male Female | 199 Participants | 67 Participants | 132 Participants |
| Sex: Female, Male Male | 206 Participants | 70 Participants | 136 Participants |
| Standard of Care Received (CRF) NAI-Containing Antiviral Therapy | 268 participants | 89 participants | 179 participants |
| Standard of Care Received (CRF) Non-NAI-Containing Antiviral Therapy | 16 participants | 9 participants | 7 participants |
| Standard of Care Received (CRF) Supportive Care/No Antiviral Therapy | 121 participants | 39 participants | 82 participants |
| Supplemental oxygen required at Screening Missing | 7 participants | 3 participants | 4 participants |
| Supplemental oxygen required at Screening Needed | 132 participants | 45 participants | 87 participants |
| Supplemental oxygen required at Screening Not needed | 266 participants | 89 participants | 177 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 42 / 134 | 63 / 264 |
| serious Total, serious adverse events | 13 / 134 | 15 / 264 |
Outcome results
Primary
Time to Clinical Resolution (Kaplan-Meier Estimate)
Time to clinical resolution was defined as the time in hours from initiation of study treatment until normalization of at least 4 of the 5 signs within the respective normalization criteria, maintained for at least 24-hours. Time to clinical resolution was summarized by treatment group using the method of Kaplan-Meier. For subjects who did not experience clinical resolution, values were censored at the date of their last non-missing assessment of clinical resolution during the study (whether this assessment occurred as an inpatient or as an outpatient).
Time frame: 10 days
Population: The Intent-to-Treat Infected-Non-NAI-Containing SOC (ITTI-Non-NAI) population included randomized subjects who received at least 1 dose of study drug, had confirmed influenza, and who received an SOC that does not contain a NAI at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo+SOC | Time to Clinical Resolution (Kaplan-Meier Estimate) | 49.5 hours |
| Peramivir+SOC | Time to Clinical Resolution (Kaplan-Meier Estimate) | 42.5 hours |
p-value: 0.97395% CI: [0.69, 1.55]Wilcoxon-Gehan statistic
Secondary
Change (Reduction) in Influenza Virus Titer
The reduction in viral shedding was assessed as the change from baseline in log10 tissue culture infective dose50 (TCID50/mL) and RT-PCR and was summarized for each treatment group and study visit.
Time frame: Baseline and 24, 48, 108 hours
Population: The Intent-to-Treat Infected-Non-NAI-Containing SOC (ITTI-Non-NAI) population included randomized subjects who received at least 1 dose of study drug, had confirmed influenza, and who received an SOC that does not contain an NAI at randomization.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo+SOC | Change (Reduction) in Influenza Virus Titer | Change from Baseline, 48 Hours | -1.67 log10 viral particles/mL |
| Placebo+SOC | Change (Reduction) in Influenza Virus Titer | Change from Baseline, 24 Hours | -1.09 log10 viral particles/mL |
| Placebo+SOC | Change (Reduction) in Influenza Virus Titer | Change from Baseline, 108 Hours | -2.39 log10 viral particles/mL |
| Peramivir+SOC | Change (Reduction) in Influenza Virus Titer | Change from Baseline, 48 Hours | -2.02 log10 viral particles/mL |
| Peramivir+SOC | Change (Reduction) in Influenza Virus Titer | Change from Baseline, 24 Hours | -1.49 log10 viral particles/mL |
| Peramivir+SOC | Change (Reduction) in Influenza Virus Titer | Change from Baseline, 108 Hours | -2.48 log10 viral particles/mL |
Secondary
Duration of All ICU Admissions (Kaplan-Meier Estimate)
Duration of postbaseline ICU admission was defined as the total number of days in the ICU for those subjects who had a post-baseline admission to the ICU. Only days starting after the initial postbaseline admission were included. If a subject's stay in the ICU was ongoing, the duration was censored at the last study visit. Subjects who did not have a postbaseline admission had a duration of 0.
Time frame: 10 days
Population: The Intent-to-Treat Infected-Non-NAI-Containing SOC (ITTI-Non-NAI) population included randomized subjects who received at least 1 dose of study drug, had confirmed influenza, and who received an SOC that does not contain an NAI at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo+SOC | Duration of All ICU Admissions (Kaplan-Meier Estimate) | 3.0 days |
| Peramivir+SOC | Duration of All ICU Admissions (Kaplan-Meier Estimate) | 3.0 days |
p-value: 0.30395% CI: [0.41, 2.98]Wilcoxon-Gehan statistic
Secondary
Number of Subjects With ICU Admission
The number of subjects requiring ICU admission post-randomization was summarized by treatment group.
Time frame: 10 days
Population: The Intent-to-Treat Infected-Non-NAI-Containing SOC (ITTI-Non-NAI) population included randomized subjects who received at least 1 dose of study drug, had confirmed influenza, and who received an SOC that does not contain an NAI at randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo+SOC | Number of Subjects With ICU Admission | At Baseline | 8 participants |
| Placebo+SOC | Number of Subjects With ICU Admission | After initiation of treatment | 1 participants |
| Placebo+SOC | Number of Subjects With ICU Admission | At any time | 9 participants |
| Peramivir+SOC | Number of Subjects With ICU Admission | At Baseline | 15 participants |
| Peramivir+SOC | Number of Subjects With ICU Admission | After initiation of treatment | 0 participants |
| Peramivir+SOC | Number of Subjects With ICU Admission | At any time | 15 participants |
Secondary
Time to Alleviation of Clinical Symptoms of Influenza
Time to alleviation of clinical symptoms of influenza was measured as the time from the first dose of study drug through the time period in which all 7 symptoms of influenza (cough, sore throat, nasal congestion, myalgia \[aches and pains\], headache, feverishness, and fatigue) were absent or rated as no greater than mild for at least 24 hours. Time to alleviation of symptoms was estimated using the method of Kaplan-Meier. Subjects who did not have resolution of any individual clinical sign were censored at the time of their last non-missing assessment of that sign.
Time frame: 10 days
Population: The Intent-to-Treat Infected-Non-NAI-Containing SOC (ITTI-Non-NAI) population included randomized subjects who received at least 1 dose of study drug, had confirmed influenza, and who received an SOC that does not contain an NAI at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo+SOC | Time to Alleviation of Clinical Symptoms of Influenza | 68.2 hours |
| Peramivir+SOC | Time to Alleviation of Clinical Symptoms of Influenza | 67.0 hours |
p-value: 0.55895% CI: [0.75, 1.72]Wilcoxon-Gehan statistic
Secondary
Time to Resolution of Fever (Kaplan-Meier Estimate)
Time to resolution of fever was measured as the time from initiation of study treatment until resolution of fever, maintained for at least 24 hours; temperature measurements taken less than 4 hours after antipyretic use were treated as missing values.
Time frame: 10 days
Population: The Intent-to-Treat Infected-Non-NAI-Containing SOC (ITTI-Non-NAI) population included randomized subjects who received at least 1 dose of study drug, had confirmed influenza, and who received an SOC that does not contain an NAI at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo+SOC | Time to Resolution of Fever (Kaplan-Meier Estimate) | 41.0 hours |
| Peramivir+SOC | Time to Resolution of Fever (Kaplan-Meier Estimate) | 42.5 hours |
p-value: 0.63395% CI: [0.59, 1.31]Wilcoxon-Gehan statistic
Secondary
Time to Resumption of Usual Activities
Time to resumption of usual activities was determined from the visual analog scale (scale ranged from 0 to 10 where 0 indicated subject was unable to perform usual activities at all and 10 indicated subject was able to perform all usual activities fully). Time to resumption of usual activities was summarized by treatment group using the method of Kaplan-Meier.
Time frame: 10 days
Population: The Intent-to-Treat Infected-Non-NAI-Containing SOC (ITTI-Non-NAI) population included randomized subjects who received at least 1 dose of study drug, had confirmed influenza, and who received an SOC that does not contain an NAI at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo+SOC | Time to Resumption of Usual Activities | 9.3 days |
| Peramivir+SOC | Time to Resumption of Usual Activities | 8.1 days |
p-value: 0.74795% CI: [0.92, 2.32]Wilcoxon-Gehan statistic
Other Pre-specified
Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial
Viral sensitivity to peramivir, oseltamivir, and zanamivir was assessed over time during the study, and was presented as fold change from initial sensitivity by influenza virus subtype. Initial assessment of susceptibility may have occurred at a post-baseline visit.
Time frame: Initial (baseline or post-baseline) and up to 10 days
Population: The Intent-to-Treat Infected (ITTI) population included randomized subjects who received at least 1 dose of study drug, and had confirmed influenza A or B.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | A: H3N2-Fold Change in Zanamivir Susceptibility | 2.70 fold change | Standard Deviation 6.563 |
| Placebo+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | A: H1N1-Fold Change in Zanamivir Susceptibility | 1.03 fold change | Standard Deviation 0.728 |
| Placebo+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | A: H3N2-Fold Change in Peramivir Susceptibility | 1.23 fold change | Standard Deviation 0.555 |
| Placebo+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | B: Fold Change in Peramivir Susceptibility | 1.01 fold change | Standard Deviation 0.331 |
| Placebo+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | A: H1N1-Fold Change in Peramivir Susceptibility | 1.12 fold change | Standard Deviation 0.879 |
| Placebo+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | B: Fold Change in Oseltamivir Susceptibility | 0.98 fold change | Standard Deviation 0.376 |
| Placebo+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | A: H3N2-Fold Change in Oseltamivir Susceptibility | 1.36 fold change | Standard Deviation 0.836 |
| Placebo+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | B: Fold Change in Zanamivir Susceptibility | 1.02 fold change | Standard Deviation 0.375 |
| Placebo+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | A: H1N1-Fold Change in Oseltamivir Susceptibility | 1.51 fold change | Standard Deviation 1.695 |
| Peramivir+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | B: Fold Change in Zanamivir Susceptibility | 1.36 fold change | Standard Deviation 0.613 |
| Peramivir+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | A: H3N2-Fold Change in Oseltamivir Susceptibility | 1.14 fold change | Standard Deviation 0.805 |
| Peramivir+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | A: H3N2-Fold Change in Zanamivir Susceptibility | 1.33 fold change | Standard Deviation 0.773 |
| Peramivir+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | A: H1N1-Fold Change in Peramivir Susceptibility | 3.63 fold change | Standard Deviation 16.333 |
| Peramivir+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | A: H1N1-Fold Change in Oseltamivir Susceptibility | 9.20 fold change | Standard Deviation 50.92 |
| Peramivir+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | A: H1N1-Fold Change in Zanamivir Susceptibility | 1.06 fold change | Standard Deviation 0.49 |
| Peramivir+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | B: Fold Change in Peramivir Susceptibility | 3.21 fold change | Standard Deviation 8.456 |
| Peramivir+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | B: Fold Change in Oseltamivir Susceptibility | 1.48 fold change | Standard Deviation 1.635 |
| Peramivir+SOC | Change in Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; Fold Change From Initial | A: H3N2-Fold Change in Peramivir Susceptibility | 1.19 fold change | Standard Deviation 0.527 |
Other Pre-specified
Incidence of Influenza-Related Complications
Influenza-related complications were defined as the occurrence of sinusitis, otitis, bronchitis, and pneumonia as reported on the influenza-related complications CRF.
Time frame: 10 days
Population: The Intent-to-Treat Infected-Non-NAI-Containing SOC (ITTI-Non-NAI) population included randomized subjects who received at least 1 dose of study drug, had confirmed influenza, and who received an SOC that does not contain an NAI at randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo+SOC | Incidence of Influenza-Related Complications | Bronchitis | 4 participants |
| Placebo+SOC | Incidence of Influenza-Related Complications | Otitis | 0 participants |
| Placebo+SOC | Incidence of Influenza-Related Complications | Pneumonia | 4 participants |
| Placebo+SOC | Incidence of Influenza-Related Complications | Sinusitis | 1 participants |
| Placebo+SOC | Incidence of Influenza-Related Complications | Any Influenza-Related Complication | 9 participants |
| Peramivir+SOC | Incidence of Influenza-Related Complications | Pneumonia | 8 participants |
| Peramivir+SOC | Incidence of Influenza-Related Complications | Sinusitis | 2 participants |
| Peramivir+SOC | Incidence of Influenza-Related Complications | Bronchitis | 5 participants |
| Peramivir+SOC | Incidence of Influenza-Related Complications | Any Influenza-Related Complication | 15 participants |
| Peramivir+SOC | Incidence of Influenza-Related Complications | Otitis | 0 participants |
p-value: 0.768Cochran-Mantel-Haenszel
Other Pre-specified
Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM)
Initial viral sensitivity to peramivir, oseltamivir, and zanamivir was assessed over time during the study, and was presented by influenza virus subtype. Initial assessment of susceptibility may have occurred at a post-baseline visit.
Time frame: Initial (baseline or post-baseline) and up to 10 days
Population: The Intent-to-Treat Infected (ITTI) population included randomized subjects who received at least 1 dose of study drug, and had confirmed influenza A or B.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | A: H3N2-Initial Oseltamivir Susceptibility | 0.30 nM | Standard Deviation 0.131 |
| Placebo+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | A: H1N1- Initial Oseltamivir Susceptibility | 1.12 nM | Standard Deviation 0.772 |
| Placebo+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | B: Initial Peramivir Susceptibility | 1.14 nM | Standard Deviation 0.625 |
| Placebo+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | A: H1N1- Initial Zanamivir Susceptibility | 0.60 nM | Standard Deviation 0.416 |
| Placebo+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | A: H3N2-Initial Peramivir Susceptibility | 0.18 nM | Standard Deviation 0.074 |
| Placebo+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | B: Initial Oseltamivir Susceptibility | 18.47 nM | Standard Deviation 4.83 |
| Placebo+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | A: H1N1- Initial Peramivir Susceptibility | 0.24 nM | Standard Deviation 0.152 |
| Placebo+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | B: Initial Zanamivir Susceptibility | 2.36 nM | Standard Deviation 1.009 |
| Placebo+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | A: H3N2-Initial Zanamivir Susceptibility | 0.34 nM | Standard Deviation 0.185 |
| Peramivir+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | B: Initial Zanamivir Susceptibility | 2.30 nM | Standard Deviation 0.958 |
| Peramivir+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | A: H3N2-Initial Zanamivir Susceptibility | 0.34 nM | Standard Deviation 0.071 |
| Peramivir+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | A: H1N1- Initial Zanamivir Susceptibility | 0.60 nM | Standard Deviation 0.402 |
| Peramivir+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | A: H3N2-Initial Oseltamivir Susceptibility | 0.31 nM | Standard Deviation 0.131 |
| Peramivir+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | A: H1N1- Initial Peramivir Susceptibility | 1.11 nM | Standard Deviation 6.181 |
| Peramivir+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | A: H1N1- Initial Oseltamivir Susceptibility | 11.03 nM | Standard Deviation 70.524 |
| Peramivir+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | B: Initial Peramivir Susceptibility | 1.15 nM | Standard Deviation 0.628 |
| Peramivir+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | B: Initial Oseltamivir Susceptibility | 21.47 nM | Standard Deviation 9.422 |
| Peramivir+SOC | Initial Viral Sensitivity to Peramivir, Oseltamivir, and Zanamivir; IC50 (nM) | A: H3N2-Initial Peramivir Susceptibility | 0.18 nM | Standard Deviation 0.044 |
Other Pre-specified
Number of Subjects Requiring More Than 5 Days of Study Drug
Subjects who had not met the protocol-defined criteria of clinical resolution on Day 5 or who had detectable virus by RT-PCR from a sample collected on Study Day 4 after dosing continued their assigned treatment for a further 5 days.
Time frame: 10 days
Population: The Intent-to-Treat Infected-Non-NAI-Containing SOC (ITTI-Non-NAI) population included randomized subjects who received at least 1 dose of study drug, had confirmed influenza, and who received an SOC that does not contain an NAI at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo+SOC | Number of Subjects Requiring More Than 5 Days of Study Drug | 3 participants |
| Peramivir+SOC | Number of Subjects Requiring More Than 5 Days of Study Drug | 6 participants |
p-value: 0.758Cochran-Mantel-Haenszel
Other Pre-specified
Survival at 14 and 28 Days After Initiation of Study Drug (Kaplan-Meier Estimate)
Survival was calculated as the number of days from initiation of study drug until death or last contact. Estimates and 95% confidence intervals were calculated using the method of Kaplan-Meier and presented by treatment group.
Time frame: 28 days
Population: The Intent-to-Treat Infected-Non-NAI-Containing SOC (ITTI-Non-NAI) population included randomized subjects who received at least 1 dose of study drug, had confirmed influenza, and who received an SOC that does not contain an NAI at randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo+SOC | Survival at 14 and 28 Days After Initiation of Study Drug (Kaplan-Meier Estimate) | 14 Day Survival | 98 Percent Survival |
| Placebo+SOC | Survival at 14 and 28 Days After Initiation of Study Drug (Kaplan-Meier Estimate) | 28 Day Survival | 98 Percent Survival |
| Peramivir+SOC | Survival at 14 and 28 Days After Initiation of Study Drug (Kaplan-Meier Estimate) | 14 Day Survival | 100 Percent Survival |
| Peramivir+SOC | Survival at 14 and 28 Days After Initiation of Study Drug (Kaplan-Meier Estimate) | 28 Day Survival | 100 Percent Survival |
Other Pre-specified
Time to Hospital Discharge
Time to hospital discharge, defined as the number of days from initiation of study treatment until the subject was discharged from the hospital, was summarized by treatment group using the method of Kaplan-Meier. Subjects who were not discharged from the hospital were censored at their last study visit.
Time frame: 10 days
Population: The Intent-to-Treat Infected-Non-NAI-Containing SOC (ITTI-Non-NAI) population included randomized subjects who received at least 1 dose of study drug, had confirmed influenza, and who received an SOC that does not contain an NAI at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo+SOC | Time to Hospital Discharge | 5.0 days |
| Peramivir+SOC | Time to Hospital Discharge | 5.0 days |