Evaluation of the Efficacy and Safety of Peramivir in Subjects With Uncomplicated Acute Influenza.

Overview

This is a study for patients with flu who also have a fever as well as other flu symptoms. Patients must have had symptoms for less than 48 hours in order to participate. Patients will have two out of three chances of getting an active study treatment and the other third will receive a placebo (dummy drug). Nobody will know who gets the active drug and who gets the inactive drug. All patients will get supplies to treat symptoms of flu. Patients will need to be seen 5 more times after they are enrolled in the study.

Full Title of Study: “A Phase II, Multicenter, Randomized, Double-Mask, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Intramuscular Peramivir in Subjects With Uncomplicated Acute Influenza.”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: September 2007

Detailed Description

Peramivir is a neuraminidase inhibitor that was previously shown to be effective in the treatment of human experimental influenza using an oral formulation. Parenteral formulations of peramivir (for intramuscular and intravenous injection) entered clinical development at the time of this Phase 2 study. A series of Phase 1 studies in human volunteers was completed that provided safety and pharmacokinetic results that supported the initiation of this Phase 2 multinational, randomized, double-mask study that compared the antiviral efficacy and safety of peramivir administered intramuscularly versus placebo in adults with uncomplicated acute influenza. Because of the unique pharmacokinetic and pharmacodynamic properties of peramivir – a long terminal half life in plasma and an extended duration of binding to the neuraminidase enzyme – subjects were randomized in a 1:1:1 ratio to receive a single dose of one of three treatments: peramivir 150 mg, peramivir 300 mg, and placebo. Study drug was administered as one 2-mL intramuscular injection in each gluteal muscle (total of 4 mL, injected in divided doses). This multinational study was originally to be conducted at approximately 80 sites in the US and Canada. When enrollment during the North American influenza season of 2006-2007 did not achieve the target, the study was extended to sites in Australia, New Zealand, South Africa, and Hong Kong.

Interventions

  • Drug: Peramivir 150 mg
    • Single dose administered as bilateral 2-mL intramuscular injections in each gluteal muscle (one injection of peramivir 150 mg and one injection of placebo).
  • Drug: Peramivir 300 mg
    • Single dose administered as bilateral 2-mL intramuscular injections in each gluteal muscle (2 injections of peramivir 150 mg).
  • Drug: Placebo
    • Single dose administered as bilateral 2-mL intramuscular injections in each gluteal muscle (2 injections of placebo).

Arms, Groups and Cohorts

  • Experimental: Peramivir 150 mg
  • Experimental: Peramivir 300 mg
  • Placebo Comparator: Placebo

Clinical Trial Outcome Measures

Primary Measures

  • Time to Alleviation of Symptoms (Kaplan-Meier Estimate)
    • Time Frame: Up to 14 days
    • Descriptive statistics for the primary efficacy variables were tabulated by treatment group. Alleviation of symptoms was determined by data recorded in the Subject Diary. Treatment differences were assessed using a Cox Regression model with effects for current smoking behavior, treatment, and geographic region. Subjects who did not experience alleviation of symptoms were censored at the date of their last assessment. A Bonferroni adjustment for the primary comparisons of each active dose with placebo was performed.

Secondary Measures

  • Time to Resolution of Fever
    • Time Frame: Up to 14 days
    • The time to resolution of fever (defined as the number of hours from initiation of study drug until temperature is less than 37.2 degrees C [99.0 degrees F] and no antipyretic medications had been taken in the previous 12 hours) was estimated using the method of Kaplan-Meier. Differences between the treatment groups were assessed using the log rank statistic controlling for current smoking behavior. Subjects who did not have resolution of fever were censored at the time of the last assessment. No adjustment for multiple comparisons was performed.
  • Time to Resumption of Ability to Perform Usual Activities
    • Time Frame: Up to 14 days
    • The time to resumption of a subject’s self-assessed ability to perform his or her usual activities was estimated using the method of Kaplan-Meier. Differences between the treatment groups were assessed using the log rank statistic controlling for current smoking behavior. Subjects who were not able to resume performance of usual activities were censored at the time of the last assessment.
  • Change From Baseline to Day 2 in Influenza Virus Titer
    • Time Frame: Baseline and approximately 24 hours after treatment
    • The change in viral titers was defined as the time-weighted change from baseline in log_10 tissue culture infective dose_50 (TCID_50/mL) and was summarized for each treatment group. The differences between the treatment groups were evaluated using a Wilcoxon Rank Sum Test controlling for current smoking behavior. Specimens for virologic culture and determination of influenza virus TCID_50/mL were obtained on Day 2 (approximately 24 hours after treatment), on Day 3 (approximately 48 hours after treatment), on Day 5 (approximately 96 hours after treatment), and on Day 9 (approximately 192 hours after treatment).
  • Change From Baseline to Day 3 in Influenza Virus Titer
    • Time Frame: Baseline and approximately 48 hours after treatment
    • The change in viral titers was defined as the time-weighted change from baseline in log_10 tissue culture infective dose_50 (TCID_50/mL) and was summarized for each treatment group. The differences between the treatment groups were evaluated using a Wilcoxon Rank Sum Test controlling for current smoking behavior. Specimens for virologic culture and determination of influenza virus TCID_50/mL were obtained on Day 2 (approximately 24 hours after treatment), on Day 3 (approximately 48 hours after treatment), on Day 5 (approximately 96 hours after treatment), and on Day 9 (approximately 192 hours after treatment).
  • Change From Baseline to Day 5 in Influenza Virus Titer
    • Time Frame: Baseline and approximately 96 hours after treatment
    • The change in viral titers was defined as the time-weighted change from baseline in log_10 tissue culture infective dose_50 (TCID_50/mL) and was summarized for each treatment group. The differences between the treatment groups were evaluated using a Wilcoxon Rank Sum Test controlling for current smoking behavior. Specimens for virologic culture and determination of influenza virus TCID_50/mL were obtained on Day 2 (approximately 24 hours after treatment), on Day 3 (approximately 48 hours after treatment), on Day 5 (approximately 96 hours after treatment), and on Day 9 (approximately 192 hours after treatment).
  • Change From Baseline to Day 9 in Influenza Virus Titer
    • Time Frame: Baseline and approximately 192 hours after treatment
    • The change in viral titers was defined as the time-weighted change from baseline in log_10 tissue culture infective dose_50 (TCID_50/mL) and was summarized for each treatment group. The differences between the treatment groups were evaluated using a Wilcoxon Rank Sum Test controlling for current smoking behavior. Specimens for virologic culture and determination of influenza virus TCID_50/mL were obtained on Day 2 (approximately 24 hours after treatment), on Day 3 (approximately 48 hours after treatment), on Day 5 (approximately 96 hours after treatment), and on Day 9 (approximately 192 hours after treatment).

Participating in This Clinical Trial

Inclusion Criteria

  • Age ≥18 years – Presence of fever at time of screening of ≥38.0 ºC (≥100.4 ºF) taken orally, or ≥38.5 ºC (≥101.2 ºF) taken rectally. However, this requirement is waived if the subject has a history of fever within the 24 hours prior to screening and has been administered antipyretic(s) in the 6 hours prior to screening. – Presence of at least one respiratory symptom (cough, sore throat, or nasal symptoms) of any severity (mild, moderate, or severe) – Presence of at least one constitutional symptom (headache, malaise, myalgia, sweats and/or chills, or fatigue) of any severity (mild, moderate, or severe) – Onset of illness no more than 48 hours before presentation. Note: Time of onset of illness is defined as either (1) the time when the temperature (either oral or rectal) was first measured as elevated (at least one ºC of elevation-oral temperature), 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. – Rapid Antigen Test (RAT) performed on an adequate specimen collected from an anterior nasal swab is positive. A negative initial RAT may be repeated within one hour of obtaining a negative result. A second negative RAT result will exclude the subject from evaluation for enrollment. – Females of childbearing potential must report one of the following: – Be surgically sterile – Have been sexually abstinent 4 weeks prior to date of screening evaluation and be willing to remain abstinent through 4 weeks after study drug administration – Use oral contraceptives or other form of hormonal birth control including hormonal vaginal rings or transdermal patches and have been using these for 3 months prior through 4 weeks after study drug administration – Use an intra-uterine device (IUD), or adequate barrier contraception (or double-barrier method such as condom or diaphragm with spermicidal gel or foam) as birth control 4 weeks prior to date of screening evaluation through 4 weeks after study drug administration. Exclusion Criteria:

  • Women who are breast-feeding – History of diagnosed chronic obstructive pulmonary disease or diagnosis of severe persistent asthma – History of chronic renal impairment requiring hemodialysis or known or suspected to have moderate or severe renal impairment (actual or estimated creatinine clearance <50 mL/min) – History of congestive heart failure requiring daily pharmacotherapy with symptoms consistent with New York Heart Association Class II, III, or IV within the past 12 months – Immunocompromised status due to illness or previous organ transplant – Current use of systemic immunosuppressive medications (except inhaled corticosteroids) – Use of rimantadine, amantadine, zanamivir, or oseltamivir in the past 7 days – Immunized against influenza with live attenuated virus vaccine (FluMist®) in the previous 21 days – Clinical evidence of active bacterial infection at any body site requiring therapy with oral or systemic antibiotics – Clinically significant signs of acute respiratory distress – Clinically significant signs of acute cardiac disease – Screening ECG which suggests acute ischemia or presence of medically significant dysrhythmia – Presence of a chronic disease or illness(es) with either clinical or historical evidence of recent exacerbation of such disease(s) or illness(es) or lack of control of such disease(s) or illness(es) – History of hepatitis B, hepatitis C, or human immunodeficiency virus infection – History of alcohol abuse or drug addiction within 1 year prior to admission in the study – Participation in a study of any investigational drug within the last 30 days – Positive urine pregnancy test

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • BioCryst Pharmaceuticals
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Stanley Block, MD, Principal Investigator, Kentucky Pediatric/Adult Research
    • James Borders, MD, Principal Investigator, Central Kentucky Research Assoc, Inc
    • Robert Broker, MD, Principal Investigator, Hillcrest Family Practice
    • Paul Browstone, MD, Principal Investigator, Alpine Clinical Research Center
    • Jeffry Jacqmein, MD, Principal Investigator, Jacksonville Center For Clinical Research
    • Isaac Marcadis, MD, Principal Investigator, Palm Beach Research Center
    • Mark Stich, MD, Principal Investigator, Jacksonville Center For Clinical Research
    • George Atiee, MD, Principal Investigator, GSA Research
    • Joe Blumenau, MD, Principal Investigator, Research Across America
    • John Champlin, MD, Principal Investigator, Medical Center
    • Shane Christensen, MD, Principal Investigator, J. Lewis Research, Inc. Foothill Family Clinic South
    • Steven Duckor, MD, Principal Investigator, Advanced Clinical Research Institute
    • Lewis Eirinberg, MD, Principal Investigator, Midwest Family Physicians
    • Milton K. Erman, MD, Principal Investigator, Pacific Sleep Medicine Services
    • Stanley Cohen, MD, Principal Investigator, Radiant Research
    • David L. Fried, MD, Principal Investigator, Omega Medical Research
    • Yury Furman, MD, Principal Investigator, Pacific Sleep Medicine Services, Inc.
    • Wayne Harper, MD, Principal Investigator, Wake Research Associates, LLC
    • Dan C Henry, MD, Principal Investigator, J. Lewis Research, Inc. Foothill Family Clinic
    • John M. Hill, MD, Principal Investigator, University Clinical Research-Deland, LLC
    • Veryl Hodges, DO, Principal Investigator, Clopton Clinic
    • Reuben Holland, III, MD, Principal Investigator, Clinical Research Center
    • William Jennings, MD, Principal Investigator, Radiant Research San Antonio
    • James Edmond Kelaher, MD,MPH, Principal Investigator, Baylor Clinic-Baylor College of Medicine
    • Allan Kelly, MD, Principal Investigator, Hermitage Medicentres
    • Ben Lasko, MD, Principal Investigator, Manna Research
    • Mark Leber, MD, Principal Investigator, The Brooklyn Hospital Center
    • Larissa Lim, MD, Principal Investigator, Florida Medical Research Institute
    • Alain Martel, MD, Principal Investigator, Clinique medicale des Campus
    • Dennis Mikolich, MD, Principal Investigator, Paragon Clinical Research, Inc.
    • Julie Mullen, MD, Principal Investigator, Sterling Research Group, LTD.
    • David Parenti, MD, Principal Investigator, George Washington University
    • Monica Pierson, MD, Principal Investigator, Radiant Research
    • Robert Poirier, MD, Principal Investigator, Barnes-Jewish Hospital Emergency Department
    • Ivan Rarick, MD, Principal Investigator, Benchmark Research
    • Dennis Riff, MD, Principal Investigator, Advanced Clinical Research Institute
    • Q Rizvi, MD, Principal Investigator, Castledowns Medicentre
    • Michael Rokeach, MD, Principal Investigator, Pacific Sleep Medicine Services
    • Rawle Seupaul, MD, Principal Investigator, Wishard Hospital
    • Daniel Shu, MD, Principal Investigator, Gain Medical Research Centre
    • Steve Sitar, MD, Principal Investigator, Orange County Clinical Trials
    • Kirk Stiffler, MD, Principal Investigator, Summa Emergency Associates Inc.
    • Guy Tellier, MD, Principal Investigator, Omnispec clinical research Inc
    • Michael Warren, MD, Principal Investigator, Research Across America at Oyster Point Family Health Center
    • Randall Watson, MD, Principal Investigator, J. Lewis Research, Inc./Southwest Family Medicine
    • John Michael Wise, MD, Principal Investigator, Bozeman Urgent Care Center
    • Chivers Woodruff, Jr., MD, Principal Investigator, Radiant Research
    • Bruce Berwald, MD, Principal Investigator, Radiant Research
    • Frank Maggiacomo, DO, Principal Investigator, New England Center for Clinical Research, Inc
    • Barry Packman, MD, Principal Investigator, Radiant Research
    • Sheila Rodstein, MD, Principal Investigator, Radiant Research, Minneapolis
    • Bernardo Ng, MD, Principal Investigator, Pacific Sleep Medicines Service
    • Gerardo Losoya, MD, Principal Investigator, Towngate Plaza Medical Center
    • Francis X. Burch, MD, Principal Investigator, Radiant Research-San Antonio Northeast
    • John P. Delgado, MD, Principal Investigator, Integrated Medical Research, PC
    • Edward Fein, MD, Principal Investigator, Pulmonary & Critical Care Associates
    • Bruce D. Forney, MD, Principal Investigator, Alliance Medical Center
    • James E. Greenwald, MD, Principal Investigator, Medex Healthcare Research, Inc.
    • Robert Hudrick, DO, Principal Investigator, University of Medicine & Dentistry of New Jersey
    • Robert Jeanfreau, MD, Principal Investigator, Benchmark Research
    • Robert Kaufmann, MD, Principal Investigator, Georgia Clinical Research
    • Sy Lam, MD, Principal Investigator, Calgary West Medical Centre Clinical Studies
    • Keith S. Reisinger, MD, MPH, Principal Investigator, Primary Physicians Research, Inc
    • Keith S. Reisinger, MD, MPH, Principal Investigator, Family Practice Medical Associates South
    • Earl Martin, MD, Principal Investigator, Dynamed Clinical Research
    • Jean-Sebastien Gauthier, MD, Principal Investigator, Q & T Research Inc.
    • Jeffrey Rosen, MD, Principal Investigator, Clinical Research of Southern Florida
    • Gerald Burns, MD, Principal Investigator, New Orleans Medical
    • Stewart Behiel, MD, Principal Investigator, Belvedere Medicentre
    • Giuseppe D’Ignazio, MD, Principal Investigator, Source Unique Clinic
    • Indravadan Dattani, MD, Principal Investigator, Prairie Clinical
    • Roy A. Gritter, MD, Principal Investigator, RJA Medicentres
    • Balbir Chahal, MD, Principal Investigator, Balbir Chahal M.D. ,P.A.

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