Trial Outcomes & Findings for 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 (NCT NCT00705406)

Last Updated: 2015-02-16

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

405 participants

Primary outcome timeframe

Information collected twice daily beginning predose on Day 1 and through Day 9, then once daily through Day 14

Results posted on

2015-02-16

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.	Peramivir 600 mg Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Overall Study STARTED	203	202
Overall Study COMPLETED	199	197
Overall Study NOT COMPLETED	4	5

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.	Peramivir 600 mg Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Overall Study Lost to Follow-up	3	3
Overall Study Did not receive study drug	1	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=203 Participants Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.	Peramivir 600 mg n=202 Participants Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.	Total n=405 Participants Total of all reporting groups
Age, Continuous	35 years STANDARD_DEVIATION 11.3 • n=5 Participants	35 years STANDARD_DEVIATION 12.1 • n=7 Participants	35 years STANDARD_DEVIATION 11.7 • n=5 Participants
Sex: Female, Male Female	104 Participants n=5 Participants	102 Participants n=7 Participants	206 Participants n=5 Participants
Sex: Female, Male Male	99 Participants n=5 Participants	100 Participants n=7 Participants	199 Participants n=5 Participants
Race/Ethnicity, Customized White or Caucasian	101 participants n=5 Participants	106 participants n=7 Participants	207 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	68 participants n=5 Participants	61 participants n=7 Participants	129 participants n=5 Participants
Race/Ethnicity, Customized Asian	15 participants n=5 Participants	15 participants n=7 Participants	30 participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	5 participants n=5 Participants	3 participants n=7 Participants	8 participants n=5 Participants
Race/Ethnicity, Customized Other	14 participants n=5 Participants	17 participants n=7 Participants	31 participants n=5 Participants
Body Mass Index (BMI)	27.5 kg/m^2 STANDARD_DEVIATION 6.73 • n=5 Participants	27.2 kg/m^2 STANDARD_DEVIATION 6.12 • n=7 Participants	27.4 kg/m^2 STANDARD_DEVIATION 6.43 • n=5 Participants
Estimated Time of Onset of Symptoms at Screening 0-12 h Ago	13 participants n=5 Participants	16 participants n=7 Participants	29 participants n=5 Participants
Estimated Time of Onset of Symptoms at Screening 12-24 h Ago	91 participants n=5 Participants	81 participants n=7 Participants	172 participants n=5 Participants
Estimated Time of Onset of Symptoms at Screening 24-36 h Ago	99 participants n=5 Participants	104 participants n=7 Participants	203 participants n=5 Participants
Estimated Time of Onset of Symptoms at Screening Data Missing	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Initial Composite Symptom Score	14 units on a scale STANDARD_DEVIATION 4.3 • n=5 Participants	14 units on a scale STANDARD_DEVIATION 3.9 • n=7 Participants	14 units on a scale STANDARD_DEVIATION 4.1 • n=5 Participants
Rapid Antigen Test (RAT) Results Positive	202 participants n=5 Participants	200 participants n=7 Participants	402 participants n=5 Participants
Rapid Antigen Test (RAT) Results No data reported	1 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants
Confirmed Influenza Infection Result Positive by PCR Only	27 participants n=5 Participants	38 participants n=7 Participants	65 participants n=5 Participants
Confirmed Influenza Infection Result Positive by Viral Culture Only	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Confirmed Influenza Infection Result Positive by PCR and Viral Culture	147 participants n=5 Participants	122 participants n=7 Participants	269 participants n=5 Participants
Confirmed Influenza Infection Result Negative by PCR and Viral Culture	28 participants n=5 Participants	40 participants n=7 Participants	68 participants n=5 Participants
Confirmed Influenza Infection Result No Result/Sample	1 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants
Current Smoking Behavior Smoker	37 participants n=5 Participants	37 participants n=7 Participants	74 participants n=5 Participants
Current Smoking Behavior Nonsmoker	166 participants n=5 Participants	165 participants n=7 Participants	331 participants n=5 Participants

PRIMARY outcome

Timeframe: Information collected twice daily beginning predose on Day 1 and through Day 9, then once daily through Day 14

Population: 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.

Outcome measures

Outcome measures
Measure	Placebo n=147 Participants Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.	Peramivir 600 mg n=132 Participants Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Time to Alleviation of Symptoms (Kaplan-Meier Estimate)	106.9 hours Interval 90.4 to 127.4	91.1 hours Interval 77.7 to 109.7

SECONDARY outcome

Timeframe: Baseline and Days 3, 4, 9

Population: 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.

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).

Outcome measures

Outcome measures
Measure	Placebo n=120 Participants Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.	Peramivir 600 mg n=97 Participants Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Change in Influenza Virus Shedding Change at Day 3	-2.00 log10(TCID50/mL) Interval -2.25 to -1.5	-2.00 log10(TCID50/mL) Interval -2.25 to -1.5
Change in Influenza Virus Shedding Change at Day 4	-2.25 log10(TCID50/mL) Interval -2.75 to -2.0	-2.25 log10(TCID50/mL) Interval -2.75 to -2.0
Change in Influenza Virus Shedding Change at Day 9	-2.75 log10(TCID50/mL) Interval -3.0 to -2.25	-2.50 log10(TCID50/mL) Interval -2.75 to -2.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Information collected predose on Day 1 and then once daily through Day 14

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=147 Participants Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.	Peramivir 600 mg n=132 Participants Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Subject's Severity of Illness (Score*Hours)	777.0 score*hours Interval 18.0 to 3542.9	713.9 score*hours Interval 23.5 to 4565.5

OTHER_PRE_SPECIFIED outcome

Timeframe: Information collected twice daily beginning predose on Day 1 and through Day 9, then once daily through Day 14

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=147 Participants Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.	Peramivir 600 mg n=132 Participants Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Time to Resolution of Fever	44.7 hours Interval 41.5 to 52.2	44.3 hours Interval 40.1 to 55.5

OTHER_PRE_SPECIFIED outcome

Timeframe: 14 days

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=149 Participants Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.	Peramivir 600 mg n=133 Participants Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Incidence of Influenza-related Complications Any Influenza-Related Complication	25 participants	29 participants
Incidence of Influenza-related Complications Otitis	2 participants	4 participants
Incidence of Influenza-related Complications Sinusitis	17 participants	13 participants
Incidence of Influenza-related Complications Bronchitis	10 participants	15 participants
Incidence of Influenza-related Complications Pneumonia	0 participants	3 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=114 Participants Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.	Peramivir 600 mg n=89 Participants Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Baseline Influenza Virus A (H1N1) Susceptibility to Neuraminidase Inhibitors (Mean IC50) A: H1N1-Baseline Peramivir Susceptibility	67.46 nM Standard Error 54.625	72.27 nM Standard Error 88.306
Baseline Influenza Virus A (H1N1) Susceptibility to Neuraminidase Inhibitors (Mean IC50) A: H1N1-Baseline Oseltamivir Susceptibility	983.41 nM Standard Error 1129.29	1007.29 nM Standard Error 1425.095
Baseline Influenza Virus A (H1N1) Susceptibility to Neuraminidase Inhibitors (Mean IC50) A: H1N1-Baseline Zanamivir Susceptibility	1.27 nM Standard Error 1.131	1.48 nM Standard Error 1.686

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and up to 14 days

Population: 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).

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.

Outcome measures

Outcome measures
Measure	Placebo n=39 Participants Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.	Peramivir 600 mg n=37 Participants Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Change in Influenza Virus A (H1N1) Susceptibility to Neuraminidase Inhibitors (Fold Change From Baseline in IC50) A: H1N1- Fold Change in Peramivir Susceptibility	1.03 Fold Change from Baseline Standard Error 0.660	1.10 Fold Change from Baseline Standard Error 0.677
Change in Influenza Virus A (H1N1) Susceptibility to Neuraminidase Inhibitors (Fold Change From Baseline in IC50) A: H1N1- Fold Change in Oseltamivir Susceptibility	1.20 Fold Change from Baseline Standard Error 1.055	1.28 Fold Change from Baseline Standard Error 1.441
Change in Influenza Virus A (H1N1) Susceptibility to Neuraminidase Inhibitors (Fold Change From Baseline in IC50) A: H1N1- Fold Change in Zanamivir Susceptibility	3.68 Fold Change from Baseline Standard Error 11.882	2.67 Fold Change from Baseline Standard Error 9.797

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and up to 14 days

Population: 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.

Outcome measures

Outcome measures
Measure	Placebo n=23 Participants Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.	Peramivir 600 mg n=24 Participants Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Baseline Influenza Virus B Susceptibility to Neuraminidase Inhibitors (Mean Baseline IC50) B: Baseline Oseltamivir Susceptibility	40.98 nM Standard Error 24.202	28.72 nM Standard Error 17.838
Baseline Influenza Virus B Susceptibility to Neuraminidase Inhibitors (Mean Baseline IC50) B: Baseline Peramivir Susceptibility	6.47 nM Standard Error 2.442	6.03 nM Standard Error 3.633
Baseline Influenza Virus B Susceptibility to Neuraminidase Inhibitors (Mean Baseline IC50) B: Baseline Zanamivir Susceptibility	5.78 nM Standard Error 2.682	4.65 nM Standard Error 2.282

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and up to 14 days

Population: 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).

Outcome measures

Outcome measures
Measure	Placebo n=8 Participants Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.	Peramivir 600 mg n=12 Participants Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Change in Influenza Virus B Susceptibility to Neuraminidase Inhibitors (Mean Baseline IC50 and Fold Change From Baseline in IC50) B: Fold Change in Peramivir Susceptibility	1.27 Fold Change from Baseline Standard Error 1.319	0.92 Fold Change from Baseline Standard Error 0.442
Change in Influenza Virus B Susceptibility to Neuraminidase Inhibitors (Mean Baseline IC50 and Fold Change From Baseline in IC50) B: Fold Change in Oseltamivir Susceptibility	1.24 Fold Change from Baseline Standard Error 0.819	0.95 Fold Change from Baseline Standard Error 0.374
Change in Influenza Virus B Susceptibility to Neuraminidase Inhibitors (Mean Baseline IC50 and Fold Change From Baseline in IC50) B: Fold Change in Zanamivir Susceptibility	1.10 Fold Change from Baseline Standard Error 0.737	0.95 Fold Change from Baseline Standard Error 0.497

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 27 other events

Deaths: 0 deaths

Peramivir 600 mg

Serious events: 0 serious events

Other events: 31 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=202 participants at risk Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.	Peramivir 600 mg n=200 participants at risk Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Infections and infestations Disseminated Tuberculosis	0.50% 1/202 • Number of events 1 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).	0.00% 0/200 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).

Other adverse events

Other adverse events
Measure	Placebo n=202 participants at risk Placebo (buffered diluent) administered as bilateral 2-mL intramuscular injection.	Peramivir 600 mg n=200 participants at risk Peramivir 600 mg administered as bilateral 2-mL intramuscular injection.
Gastrointestinal disorders Nausea	5.0% 10/202 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).	3.5% 7/200 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).
Gastrointestinal disorders Diarrhoea	4.0% 8/202 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).	3.0% 6/200 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).
Gastrointestinal disorders Vomiting	0.00% 0/202 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).	2.0% 4/200 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).
Investigations Blood creatine phosphokinase increased	0.50% 1/202 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).	5.5% 11/200 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).
General disorders Injection site pain	0.99% 2/202 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).	2.0% 4/200 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).
Infections and infestations Urinary tract infection	2.5% 5/202 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).	0.50% 1/200 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).
Nervous system disorders Headache	2.5% 5/202 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).	0.00% 0/200 • Treatment-emergent AEs included any AEs that occurred after treatment on Day 1 and up to and including the visit on Day 14. 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).

Additional Information

William P. Sheridan, MBBS

BioCryst Pharmaceuticals, Inc.

Phone: 919-859-1302

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place