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A Phase II, Multicenter, Randomized, Placebo -Controlled, Study To Evaluate The Efficacy and Safety Of Intramuscular Peramivir 600 mg In Subjects With Uncomplicated Acute Influenza

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00705406
Recruitment Status : Completed
First Posted : June 26, 2008
Results First Posted : February 16, 2015
Last Update Posted : February 16, 2015
Sponsor:
Information provided by (Responsible Party):
BioCryst Pharmaceuticals

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Acute, Uncomplicated Human Influenza
Interventions Drug: Peramivir
Drug: Placebo
Enrollment 405
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo Peramivir 600 mg
Hide Arm/Group Description Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection. Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Period Title: Overall Study
Started 203 202
Completed 199 197
Not Completed 4 5
Reason Not Completed
Lost to Follow-up             3             3
Did not receive study drug             1             2
Arm/Group Title Placebo Peramivir 600 mg Total
Hide Arm/Group Description Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection. Peramivir 600 mg administered as bilateral 2-mL intramuscular injection. Total of all reporting groups
Overall Number of Baseline Participants 203 202 405
Hide Baseline Analysis Population Description
Intent-to-Treat (ITT)
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 203 participants 202 participants 405 participants
35  (11.3) 35  (12.1) 35  (11.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 203 participants 202 participants 405 participants
Female
104
  51.2%
102
  50.5%
206
  50.9%
Male
99
  48.8%
100
  49.5%
199
  49.1%
Race/Ethnicity, Customized   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 203 participants 202 participants 405 participants
White or Caucasian 101 106 207
Black or African American 68 61 129
Asian 15 15 30
American Indian or Alaska Native 5 3 8
Other 14 17 31
[1]
Measure Description: Participants may have been counted in more than 1 category; therefore, numbers may add up to more than the total number of participants.
Body Mass Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 203 participants 202 participants 405 participants
27.5  (6.73) 27.2  (6.12) 27.4  (6.43)
Estimated Time of Onset of Symptoms at Screening  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 203 participants 202 participants 405 participants
0-12 h Ago 13 16 29
12-24 h Ago 91 81 172
24-36 h Ago 99 104 203
Data Missing 0 1 1
Initial Composite Symptom Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 203 participants 202 participants 405 participants
14  (4.3) 14  (3.9) 14  (4.1)
[1]
Measure Description: Initial Composite Symptom Score is defined as the sum of the 7 symptoms of influenza initially recorded by the subject in the diary (cough; sore throat; nasal congestion; myalgia [aches and pains]; headache; feverishness; and fatigue), each graded on a 4-point severity scale [0, absent; 1, mild; 2, moderate; 3, severe]); for the composite score, individual scores were summed, with a range from 0 to 21.
Rapid Antigen Test (RAT) Results   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 203 participants 202 participants 405 participants
Positive 202 200 402
No data reported 1 2 3
[1]
Measure Description: Positive influenza infection confirmed by PCR or virus culture.
Confirmed Influenza Infection Result  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 203 participants 202 participants 405 participants
Positive by PCR Only 27 38 65
Positive by Viral Culture Only 0 0 0
Positive by PCR and Viral Culture 147 122 269
Negative by PCR and Viral Culture 28 40 68
No Result/Sample 1 2 3
Current Smoking Behavior  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 203 participants 202 participants 405 participants
Smoker 37 37 74
Nonsmoker 166 165 331
1.Primary Outcome
Title Time to Alleviation of Symptoms (Kaplan-Meier Estimate)
Hide Description The primary efficacy endpoint was the time to alleviation of symptoms calculated as the number of hours from initiation of study drug until the start of the time period in which all 7 symptoms of influenza were either absent or present at a level no greater than mild for at least 21.5 (24 hours - 10%) hours. Subjects with missing diary data were excluded and those who did not experience alleviation of symptoms were censored at the last observed symptom assessment.
Time Frame Information collected twice daily beginning predose on Day 1 and through Day 9, then once daily through Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The Intent-to-Treat Infected with Influenza A (ITTI-A) population included all subjects who were randomized, received study drug, and had confirmed influenza A by culture or PCR.
Arm/Group Title Placebo Peramivir 600 mg
Hide Arm/Group Description:
Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.
Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Overall Number of Participants Analyzed 147 132
Median (95% Confidence Interval)
Unit of Measure: hours
106.9
(90.4 to 127.4)
91.1
(77.7 to 109.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Peramivir 600 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.222
Comments [Not Specified]
Method Wilcoxon-Gehan test statistic
Comments P-value is from a Wilcoxon-Gehan test statistic controlling for smoking status and hemisphere of enrollment.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.927
Confidence Interval (2-Sided) 95%
0.723 to 1.188
Estimation Comments Hazard Ratio and corresponding 95% CI are based the Cox Regression Model including parameters for treatment, controlling for smoking status and hemisphere of enrollment.
2.Secondary Outcome
Title Change in Influenza Virus Shedding
Hide Description Changes from Baseline in log10 TCID50/mL through Days 3, 4, and 9 were presented by treatment group for subjects with positive viral titers at Baseline (log10 TCID50/mL >0.5).
Time Frame Baseline and Days 3, 4, 9
Hide Outcome Measure Data
Hide Analysis Population Description
The Intent-to-Treat Infected Influenza A (ITTI-A) population included all subjects who were randomized, received study drug, and had confirmed influenza A infection by culture or PCR.
Arm/Group Title Placebo Peramivir 600 mg
Hide Arm/Group Description:
Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.
Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Overall Number of Participants Analyzed 120 97
Median (95% Confidence Interval)
Unit of Measure: log10(TCID50/mL)
Change at Day 3
-2.00
(-2.25 to -1.50)
-2.00
(-2.25 to -1.50)
Change at Day 4
-2.25
(-2.75 to -2.00)
-2.25
(-2.75 to -2.00)
Change at Day 9
-2.75
(-3.00 to -2.25)
-2.50
(-2.75 to -2.00)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Peramivir 600 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.05
Comments [Not Specified]
Method van Elteren test
Comments P-value for comparisons at all time points. P-value was based on the van Elteren test controlling for smoking status and hemisphere of enrollment.
3.Other Pre-specified Outcome
Title Subject's Severity of Illness (Score*Hours)
Hide Description

A subject's severity of illness (area under the symptom score curve, as measured in score-hours) was assessed using available symptom score data until the time of alleviation of symptoms.The score-hours were calculated as the product of the daily symptom score times the hours to alleviation. All available data until time of alleviation were utilized.

The daily symptom score was defined as the sum of the 7 symptoms of influenza recorded by the subject in the diary each day (cough; sore throat; nasal congestion; myalgia [aches and pains]; headache; feverishness; and fatigue), each graded on a 4-point severity scale [0, absent; 1, mild; 2, moderate; 3, severe]); for the composite score, individual scores were summed, with a range from 0 to 21.

Time Frame Information collected predose on Day 1 and then once daily through Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The Intent-to-Treat Infected Influenza A (ITTI-A) population included all subjects who were randomized, received study drug, and had confirmed influenza A infection by culture or PCR.
Arm/Group Title Placebo Peramivir 600 mg
Hide Arm/Group Description:
Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.
Peramivir 600 mg administered as bilateral 2-mL intramuscular injection
Overall Number of Participants Analyzed 147 132
Median (Full Range)
Unit of Measure: score*hours
777.0
(18.0 to 3542.9)
713.9
(23.5 to 4565.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Peramivir 600 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.421
Comments [Not Specified]
Method van Elteren test
Comments P-value is based on van Elteren test controlling for smoking status and hemisphere of enrollment.
4.Other Pre-specified Outcome
Title Time to Resolution of Fever
Hide Description Time to resolution of fever was defined as the number of hours from initiation of study drug until temperature was less than 37.2 °C (99.0 °F) and no antipyretic medication had been taken for at least 12 hours.
Time Frame Information collected twice daily beginning predose on Day 1 and through Day 9, then once daily through Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The Intent-to-Treat Infected Influenza A (ITTI-A) population included all subjects who were randomized, received study drug, and had confirmed influenza A infection by culture or PCR.
Arm/Group Title Placebo Peramivir 600 mg
Hide Arm/Group Description:
Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.
Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Overall Number of Participants Analyzed 147 132
Median (95% Confidence Interval)
Unit of Measure: hours
44.7
(41.5 to 52.2)
44.3
(40.1 to 55.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Peramivir 600 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.885
Comments [Not Specified]
Method Wilcoxon-Gehan test statistic
Comments P-values are from a Wilcoxon-Gehan test statistic controlling for smoking status and hemisphere of enrollment.
5.Other Pre-specified Outcome
Title Incidence of Influenza-related Complications
Hide Description Study personnel were provided with an IRC checklist in the CRF to evaluate the subject for the presence of clinical signs and/or symptoms of the following IRCs: sinusitis, otitis, bronchitis, and pneumonia. Subjects with clinical signs and/or symptoms consistent with these conditions at Screening were not eligible for enrollment in this study.
Time Frame 14 days
Hide Outcome Measure Data
Hide Analysis Population Description
The Intent-to-Treat Infected Influenza A (ITTI-A) population included all subjects who were randomized, received study drug, and had confirmed influenza A infection by culture or PCR.
Arm/Group Title Placebo Peramivir 600 mg
Hide Arm/Group Description:
Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.
Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Overall Number of Participants Analyzed 149 133
Measure Type: Number
Unit of Measure: participants
Any Influenza-Related Complication 25 29
Otitis 2 4
Sinusitis 17 13
Bronchitis 10 15
Pneumonia 0 3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Peramivir 600 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.306
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments P-value is based on the Cochran-Mantel-Haenszel general association test controlling for smoking status and hemisphere of enrollment.
6.Other Pre-specified Outcome
Title Baseline Influenza Virus A (H1N1) Susceptibility to Neuraminidase Inhibitors (Mean IC50)
Hide Description Baseline value of influenza virus susceptibility to neuraminidase inhibitors was assessed using virology laboratory tests. Virology laboratory tests included phenotypic characterizations of influenza virus recovered (hemagglutinin and neuraminidase) and viral susceptibility to zanamivir, oseltamivir, and peramivir, as well as genotyping of virus isolates.
Time Frame Baseline
Hide Outcome Measure Data
Hide Analysis Population Description
A subgroup of the Intent-to-Treat Infected Influenza A (ITTI-A) population that included all subjects who were randomized, received study drug, and had confirmed influenza A (H1N1) infection by culture or PCR. N was 113 for zanamivir susceptibility in the Placebo group.
Arm/Group Title Placebo Peramivir 600 mg
Hide Arm/Group Description:
Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.
Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Overall Number of Participants Analyzed 114 89
Mean (Standard Error)
Unit of Measure: nM
A: H1N1-Baseline Peramivir Susceptibility 67.46  (54.625) 72.27  (88.306)
A: H1N1-Baseline Oseltamivir Susceptibility 983.41  (1129.29) 1007.29  (1425.095)
A: H1N1-Baseline Zanamivir Susceptibility 1.27  (1.131) 1.48  (1.686)
7.Other Pre-specified Outcome
Title Change in Influenza Virus A (H1N1) Susceptibility to Neuraminidase Inhibitors (Fold Change From Baseline in IC50)
Hide Description Change from Baseline to last positive value of influenza virus susceptibility to neuraminidase inhibitors was assessed using virology laboratory tests. Virology laboratory tests included phenotypic characterizations of influenza virus recovered (hemagglutinin and neuraminidase) and viral susceptibility to zanamivir, oseltamivir, and peramivir, as well as genotyping of virus isolates. These analyses were presented separately by treatment group and viral subtype.
Time Frame Baseline and up to 14 days
Hide Outcome Measure Data
Hide Analysis Population Description
A subgroup of the Intent-to-Treat Infected Influenza A (ITTI-A) population that included all subjects who were randomized, received study drug, and had confirmed influenza A (H1N1) infection by culture or PCR. N is for fold change (participants who had baseline and last positive susceptibility values to zanamivir, oseltamivir, and peramivir).
Arm/Group Title Placebo Peramivir 600 mg
Hide Arm/Group Description:
Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.
Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Overall Number of Participants Analyzed 39 37
Mean (Standard Error)
Unit of Measure: Fold Change from Baseline
A: H1N1- Fold Change in Peramivir Susceptibility 1.03  (0.660) 1.10  (0.677)
A: H1N1- Fold Change in Oseltamivir Susceptibility 1.20  (1.055) 1.28  (1.441)
A: H1N1- Fold Change in Zanamivir Susceptibility 3.68  (11.882) 2.67  (9.797)
8.Other Pre-specified Outcome
Title Baseline Influenza Virus B Susceptibility to Neuraminidase Inhibitors (Mean Baseline IC50)
Hide Description Baseline value of influenza virus susceptibility to neuraminidase inhibitors was assessed using virology laboratory tests. Virology laboratory tests included phenotypic characterizations of influenza virus recovered (hemagglutinin and neuraminidase) and viral susceptibility to zanamivir, oseltamivir, and peramivir, as well as genotyping of virus isolates. Baseline was defined as the last non-missing value occuring prior to the initiation of study drug.
Time Frame Baseline and up to 14 days
Hide Outcome Measure Data
Hide Analysis Population Description
A subgroup of the Intent-to-Treat Infected (ITTI) population that included all subjects who were randomized, received study drug, and had confirmed influenza B infection by culture or PCR. The n reported is the number of participants who had baseline susceptibility values to zanamivir, oseltamivir, and peramivir.
Arm/Group Title Placebo Peramivir 600 mg
Hide Arm/Group Description:
Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.
Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Overall Number of Participants Analyzed 23 24
Mean (Standard Error)
Unit of Measure: nM
B: Baseline Peramivir Susceptibility 6.47  (2.442) 6.03  (3.633)
B: Baseline Oseltamivir Susceptibility 40.98  (24.202) 28.72  (17.838)
B: Baseline Zanamivir Susceptibility 5.78  (2.682) 4.65  (2.282)
9.Other Pre-specified Outcome
Title Change in Influenza Virus B Susceptibility to Neuraminidase Inhibitors (Mean Baseline IC50 and Fold Change From Baseline in IC50)
Hide Description Change from Baseline to last positive value of influenza virus susceptibility to neuraminidase inhibitors was assessed using virology laboratory tests. Virology laboratory tests included phenotypic characterizations of influenza virus recovered (hemagglutinin and neuraminidase) and viral susceptibility to zanamivir, oseltamivir, and peramivir, as well as genotyping of virus isolates. These analyses were presented separately by treatment group and viral subtype. Baseline was defined as the last non-missing value occuring prior to the initiation of study drug.
Time Frame Baseline and up to 14 days
Hide Outcome Measure Data
Hide Analysis Population Description
A subgroup of the Intent-to-Treat Infected (ITTI) population that included all subjects who were randomized, received study drug, and had confirmed influenza B infection by culture or PCR. The n reported is the number for fold change (participants who had baseline and last positive susceptibility values to zanamivir, oseltamivir, and peramivir).
Arm/Group Title Placebo Peramivir 600 mg
Hide Arm/Group Description:
Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.
Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Overall Number of Participants Analyzed 8 12
Mean (Standard Error)
Unit of Measure: Fold Change from Baseline
B: Fold Change in Peramivir Susceptibility 1.27  (1.319) 0.92  (0.442)
B: Fold Change in Oseltamivir Susceptibility 1.24  (0.819) 0.95  (0.374)
B: Fold Change in Zanamivir Susceptibility 1.10  (0.737) 0.95  (0.497)
Time Frame Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14.
Adverse Event Reporting Description Three of 405 subjects were randomized but did not receive treatment and were therefore not included in the safety population (N = 402; 202 in the Placebo group and 200 in the Peramivir 600 mg group).
 
Arm/Group Title Placebo Peramivir 600 mg
Hide Arm/Group Description Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection. Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
All-Cause Mortality
Placebo Peramivir 600 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Placebo Peramivir 600 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/202 (0.50%)      0/200 (0.00%)    
Infections and infestations     
Disseminated Tuberculosis  1  1/202 (0.50%)  1 0/200 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Placebo Peramivir 600 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   27/202 (13.37%)      31/200 (15.50%)    
Gastrointestinal disorders     
Nausea  1  10/202 (4.95%)  7/200 (3.50%) 
Diarrhoea  1  8/202 (3.96%)  6/200 (3.00%) 
Vomiting  1  0/202 (0.00%)  4/200 (2.00%) 
General disorders     
Injection site pain  1  2/202 (0.99%)  4/200 (2.00%) 
Infections and infestations     
Urinary tract infection  1  5/202 (2.48%)  1/200 (0.50%) 
Investigations     
Blood creatine phosphokinase increased  1  1/202 (0.50%)  11/200 (5.50%) 
Nervous system disorders     
Headache  1  5/202 (2.48%)  0/200 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.0
The majority of the subjects enrolled in this study with a laboratory confirmed influenza infection were infected with an influenza A/H1N1 virus containing an H275Y mutation associated with reduced susecptibility to peramivir and oseltamivir.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: William P. Sheridan, MBBS
Organization: BioCryst Pharmaceuticals, Inc.
Phone: 919-859-1302
Layout table for additonal information
Responsible Party: BioCryst Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00705406    
Other Study ID Numbers: BCX1812-212
HHS 0100200700032C ( Other Grant/Funding Number: HHS-BARDA )
First Submitted: June 24, 2008
First Posted: June 26, 2008
Results First Submitted: January 16, 2015
Results First Posted: February 16, 2015
Last Update Posted: February 16, 2015