A Study to Evaluate the Efficacy and Safety of IV Peramivir in Addition to Standard of Care Compared to Standard of Care Alone in Adults and Adolescents Who Are Hospitalized Due to Influenza

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Cough, Sore Throat, Nasal Congestion, Headache, Fever, Seasonal Influenza

Intervention / Treatment
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* Drug: Peramivir+SOC
* Drug: Placebo+SOC


Participation Criteria
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Eligibility Criteria
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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: Oral temperature ≥ 38.0 °C (≥100.4 °F), ≥38.6°C (≥101.4 °F) tympanic or rectal OR Oxygen saturation <92%, OR 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: 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 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.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Peramivir+SOC<br>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. | Drug: Peramivir+SOC<br>* 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.<br>|
| Placebo Comparator: Placebo+SOC<br>Placebo Peramivir (BCX1812) administered intravenously, once daily (every 24 hrs) for 5 days (5 doses) in addition to institution's standard of care. | Drug: Placebo+SOC<br>* Placebo Peramivir (BCX1812) administered intravenously, once daily (every 24 hrs) for 5 days (5 doses) in addition to institution's standard of care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and 24, 48, 108 hours | 
| 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. | 10 days | 
| 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. | 10 days | 
| 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. | 10 days | 
| Number of Subjects With ICU Admission | The number of subjects requiring ICU admission post-randomization was summarized by treatment group. | 10 days | 
| 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. | 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Influenza, Hospitalized, Antiviral, Flu