Clinical trial NCT01014988: Safety Study to Assess IV Zanamivir for Treatment of Influenza Infection in Patients Who Are in Hospital
Official title: An Open-label, Multi-center, Single Arm Study to Evaluate the Safety and Tolerability of Intravenous Zanamivir in the Treatment of Hospitalized Adult, Adolescent and Pediatric Subjects With Confirmed Influenza Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Influenza, Human
Keywords: pandemic
seasonal influenza
Influenza B virus
H1N1
zanamivir
Influenza A virus, H1N1 Subtype
Relenza
influenza
neuraminidase inhibitor
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-11-17
Enrollment: 202
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether zanamivir aqueous solution given by intravenous injection is safe in treating hospitalized patients with confirmed influenza infection. A single arm open-label design has been selected to achieve the primary objective of providing regulatory authorities with safety data on IV zanamivir.

Detailed description: This study will be an open-label, Phase II, multi-center, single arm study to evaluate the safety and tolerability of IV zanamivir 600mg twice daily for 5 days in hospitalized subjects with laboratory confirmed influenza infection. The initial 5-day treatment course may be extended for up to 5 additional days if viral shedding is determined to be ongoing or if clinical symptoms warrant further treatment with IV zanamivir.

Approximately 200 subjects will be enrolled into the study (approximately 150 adult/adolescent subjects and approximately 50 pediatric subjects). Adult (\>/= 18 years of age) with normal renal function will receive 600mg per dose. Pediatric (6 months to \<13 years)/adolescent (\>13 years to \<18 years) subjects will receive an age-adjusted, weight-based dose (not to exceed the 600 mg adult dose) intended to provide comparable systemic exposures to 600mg in adults. Subjects with renal impairment will receive an adjusted dose based on calculated creatinine clearance and renal replacement modality.

Serum pharmacokinetic assessments will be performed in subjects across all age groups wherever possible. Pharmacokinetic analyses will be conducted, in real-time to the extent possible, when 4 subjects (from whom samples can be obtained) are enrolled in each of the following age cohorts: 6 months to less than 1 year; 1 to less than 2 years, and 2 to less than 6 years to determine the need for pediatric dose adjustments. PK assessments are required in the first 4 subjects enrolled in the 6 months to less than 1 year age cohort, and PK data must be analyzed and IV zanamivir dosage must be reviewed before additional subjects in this age cohort can be enrolled.

The study duration is approximately 28 days for subjects whose treatment duration is 5 days, and up to approximately 33 days for subjects whose treatment duration is extended to a maximum of 10 days. The study will consist of Pre-dose Baseline Assessments (Day 1), During Treatment Assessments (Days 1 to 5, and up to Day 10), and Follow-up Assessments on the following days: Post-Treatment +2 +5, +9, +16 and +23 Days. If the first dose of IV zanamivir is administered in the afternoon/evening of Day 1, the twice daily dosing schedule will result in one treatment day encompassing two calendar days. For subjects who have been discharged from hospital, the Post-Treatment +2, +5, +9 and +16 Days Assessments can be made by telephone contact.

Eligibility criteria: Inclusion Criteria:

* Male or female aged greater than or equal to 6 months of age; a female is eligible to enter and participate in the study if she is:

  1. of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal); or,
  2. of child-bearing potential, has a negative pregnancy test at Baseline, and agrees to one of the following methods for avoidance of pregnancy during the study and until the Post-Treatment +23 Days Follow-up Assessment:
* Abstinence; or,
* Oral contraceptive, either combined or progestogen alone; or,
* Injectable progestogen; or,
* Implants of levonorgestrel; or,
* Estrogenic vaginal ring; or,
* Percutaneous contraceptive patches; or
* Intrauterine device (IUD) or intrauterine system (IUS) showing that the expected failure rate is less than 1% per year as stated in the IUD or IUS Product Label; or,
* Has a male partner who is sterilized; or,
* Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository).
* Subjects who have confirmed influenza as determined by a positive result in a rapid test for influenza A or influenza B, or a laboratory test for influenza including influenza virus antigen test, virus culture or RT-PCR test. Subjects with negative rapid test result suspected of having influenza can be enrolled following confirmatory testing by RT-PCR, antigen test or culture.
* Hospitalized subjects with symptomatic influenza
* Subjects who are able to receive their first dose of study medication within seven days of experiencing influenza-like symptoms.
* Subjects willing and able to adhere to the procedures stated in the protocol.
* Subjects/legally acceptable representative (LAR) of minors and unconscious adults willing and able to give written informed consent to participate in the study (or included as permitted by local regulatory authorities, IRBs/IECs or local laws).
* French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
* UK subjects and subjects in Spain: Subjects should be in a high dependency or intensive care setting at the time of enrollment and either have severe and progressive illness on approved influenza antivirals, or are considered unsuitable for treatment with approved influenza antivirals.
* Subjects who have severe or progressive influenza illness on approved (fully licensed) influenza antivirals, or who are considered unsuitable or inappropriate for treatment with approved influenza antivirals, or who in the opinion of the investigator may benefit from IV zanamivir therapy.

Exclusion Criteria:

* Subjects who, in the opinion of the investigator, are not likely to survive the next 48 hours beyond Baseline.
* Subjects who require concurrent therapy with another influenza antiviral drug.
* Subjects who have participated in a study using an investigational influenza antiviral drug within 30 days prior to Baseline.
* Subjects who are known or suspected to be hypersensitive to any component of the study medication.
* Subjects who meet the following criteria at Baseline:
* ALT greater than or equal to 3xULN and bilirubin greater than or equal to 2xULN or ALT greater than or equal to 5xULN
* History of cardiac disease or clinically significant arrhythmia (either on ECG or by history) which, in the opinion of the Investigator, will interfere with the safety of the individual subject.
* Child in care (CiC) as defined below:

A child who has been placed under the control or protection of an agency, organization, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation.

The definition of a CiC can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. The definition of a CiC does not include a child who is adopted or has an appointed legal guardian.

* French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days.
* Females who are pregnant (positive urine or serum pregnancy test at Baseline) or are breastfeeding.

Primary outcomes:
measure: Number of Participants With Any Adverse Event (AE) Considered to be Related to Study Treatment
timeFrame: Up to post-treatment (PT) + 23 days
measure: Number of Participants With Any Severe or Grade 3/4 AEs
timeFrame: Up to post-treatment (PT) + 23 days
measure: Number of Participants With Any Severe or Grade 3/4 Treatment-related AE
timeFrame: Up to post-treatment (PT) + 23 days
measure: Number of Participants Who Permanently Discontinued the Study Treatment Due to an AE
timeFrame: Up to 10 days
measure: Number of Participants Who Were Permanently Discontinued From the Study Due to an AE
timeFrame: Up to post-treatment (PT) + 23 days
measure: Number of Participants With the Indicated Clinical Chemistry Values Relative to the Normal Range at Baseline (Day 1) and Day 5
timeFrame: Baseline (Day 1) and Day 5
measure: Number of Participants With the Indicated Hematology Values Relative to the Normal Range at Baseline (Day 1) and Day 5
timeFrame: Baseline (Day 1) and Day 5
measure: Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Clinical Chemistry Toxicities
timeFrame: Up to post-treatment (PT) + 23 days
measure: Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Hematology Toxicities
timeFrame: Up to post-treatment (PT) + 23 days
measure: Median Heart Rate at Baseline (Day 1) and Day 5
timeFrame: Baseline (Day 1) and Day 5
measure: Median Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Baseline (Day 1) and Day 5
timeFrame: Baseline (Day 1) and Day 5
measure: Median Oxygen Saturation Measured Via Transcutaneous Oximetry (TCPO2) at Baseline (Day 1) and Day 5
timeFrame: Baseline (Day 1) and Day 5
measure: Median Respiration Rate at Baseline (Day 1) and Day 5
timeFrame: Baseline (Day 1) and Day 5
measure: Median Body Temperature at Baseline (Day 1) and Day 5
timeFrame: Baseline (Day 1) and Day 5
measure: Number of Participants Assessed as Normal/Abnormal (Clinically Significant [CS] and Not Clinically Significant [NCS]) for 12-lead Electrocardiogram (ECG) at Baseline (Day 1)
timeFrame: Baseline (Day 1)
measure: Median Corrected QT Interval (QTc) for Heart Rate by Fridericia's Formula (QTcF) and Bazett's Formula (QTcB) at Baseline (Day 1) and Day 5
timeFrame: Baseline (Day 1) and Day 5
Secondary outcomes:
measure: Median Time to Virologic Improvement
timeFrame: Up to post-treatment (PT) + 23 days
measure: Median Change From Baseline (Influenza A or B Quantitative PCR, as Appropriate) in Viral Load at the Indicated Time Points
timeFrame: Baseline (Day 1); Days 2, 3, 4, 5, 7, and 10; and post-treatment +2, +5, +9, +16, +23 days
measure: Mean Viral Susceptibility to Zanamivir at Baseline (Day 1) and All Post-Baseline Visits Collectively
timeFrame: Baseline and up to post-treatment (PT) + 23 days
measure: Number of Participants With Treatment-emergent (TE) Mutations
timeFrame: Baseline and up to post-treatment (PT) + 23 days
measure: Median Time to Resolution of Individual Vital Signs
timeFrame: Up to post-treatment (PT) + 23 days
measure: Number of Participants With the Indicated Ventilation Status: Modality of Supplemental Oxygen Delivery and Mechanical Ventilation
timeFrame: Up to post-treatment (PT) + 23 days
measure: Duration of Mechanical Ventilation and Supplemental Oxygen Use
timeFrame: Up to discharge from the hospital
measure: Median Time to Return to Pre-morbid Functional Status
timeFrame: Up to post-treatment (PT) + 23 days
measure: Number of Participants With the Indicated Mortality Status at Day 14 and Day 28
timeFrame: Day 14 and Day 28
measure: Median Time to Clinical Response (Sustained Resolution) of All Vital Signs (Composite)
timeFrame: Up to post-treatment (PT) + 23 days
measure: Number of Participants With Any AE Categorized as an Influenza Complication
timeFrame: Up to post-treatment (PT) + 23 days
measure: Number of Participants Who Used Any Concomitant Antibiotic Medications for Complications of Influenza
timeFrame: Up to post-treatment (PT) + 23 days
measure: Median Duration of Hospitalization and Intensive Care Unit (ICU) Stays
timeFrame: Up to discharge from hospital
measure: Geometric Mean Maximum Serum Concentration (Cmax) of Zanamivir at the End of Infusion
timeFrame: Day 1 and Days 3, 4, or 5
measure: Geometric Mean Area Under the Serum Drug Concentration-time Curve (AUC) Over a 12-hour Dosing Interval (AUC[0-tau]) and AUC Extrapolated to Infinity (AUC[0-inf]) of Zanamivir
timeFrame: Day 1 and Days 3, 4, or 5
measure: Geometric Mean Terminal Half Life (t1/2) of Zanamivir
timeFrame: Day 1 and Days 3, 4, or 5
measure: Geometric Mean Serum Clearance of Zanamivir
timeFrame: Day 1 and Days 3, 4, or 5
measure: Geometric Mean Volume of Distribution (Vd) of Zanamivir
timeFrame: Day 1 and Days 3, 4, or 5
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
city: Little Rock
country: United States
facility: GSK Investigational Site
state: Arkansas
city: San Diego
country: United States
facility: GSK Investigational Site
state: California
city: Stamford
country: United States
facility: GSK Investigational Site
state: Connecticut
city: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Gainesville
country: United States
facility: GSK Investigational Site
state: Florida
city: Tampa
country: United States
facility: GSK Investigational Site
state: Florida
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Decatur
country: United States
facility: GSK Investigational Site
state: Georgia
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: Topeka
country: United States
facility: GSK Investigational Site
state: Kansas
city: Louisville
country: United States
facility: GSK Investigational Site
state: Kentucky
city: New Orleans
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: St. Paul
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Kansas City
country: United States
facility: GSK Investigational Site
state: Missouri
city: St. Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: Butte
country: United States
facility: GSK Investigational Site
state: Montana
city: Camden
country: United States
facility: GSK Investigational Site
state: New Jersey
city: New Hyde Park
country: United States
facility: GSK Investigational Site
state: New York
city: Chapel Hill
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Cleveland
country: United States
facility: GSK Investigational Site
state: Ohio
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Toledo
country: United States
facility: GSK Investigational Site
state: Ohio
city: Portland
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facility: GSK Investigational Site
state: Oregon
city: Philadelphia
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facility: GSK Investigational Site
state: Pennsylvania
city: Pittsburgh
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facility: GSK Investigational Site
state: Pennsylvania
city: Memphis
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facility: GSK Investigational Site
state: Tennessee
city: Memphis
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facility: GSK Investigational Site
state: Tennessee
city: Dallas
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state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Fort Worth
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
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facility: GSK Investigational Site
state: Texas
city: Salt Lake City
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facility: GSK Investigational Site
state: Utah
city: Richmond
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facility: GSK Investigational Site
state: Virginia
city: Milwaukee
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Garran
country: Australia
facility: GSK Investigational Site
state: Australian Capital Territory
city: Chermside
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Herston
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Adelaide
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Bedford Park
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Heidelberg
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Perth
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Subiaco
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Sao Paulo
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: Rio de Janeiro
country: Brazil
facility: GSK Investigational Site
city: Winnipeg
country: Canada
facility: GSK Investigational Site
state: Manitoba
city: Halifax
country: Canada
facility: GSK Investigational Site
state: Nova Scotia
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Chicoutimi
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Quebec
country: Canada
facility: GSK Investigational Site
city: Bron cedex
country: France
facility: GSK Investigational Site
city: Grenoble cedex 9
country: France
facility: GSK Investigational Site
city: Limoges cedex
country: France
facility: GSK Investigational Site
city: Nancy cedex
country: France
facility: GSK Investigational Site
city: Nice
country: France
facility: GSK Investigational Site
city: Nîmes cedex 9
country: France
facility: GSK Investigational Site
city: Orléans cedex 2
country: France
facility: GSK Investigational Site
city: Paris cedex 14
country: France
facility: GSK Investigational Site
city: Paris
country: France
facility: GSK Investigational Site
city: Tours cedex 9
country: France
facility: GSK Investigational Site
city: Shatin
country: Hong Kong
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Hokkaido
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Yamanashi
country: Japan
facility: GSK Investigational Site
city: Bergen
country: Norway
facility: GSK Investigational Site
city: Trondheim
country: Norway
facility: GSK Investigational Site
city: Ekaterinburg
country: Russian Federation
facility: GSK Investigational Site
city: Smolensk
country: Russian Federation
facility: GSK Investigational Site
city: Middelburg
country: South Africa
facility: GSK Investigational Site
state: Mpumalanga
city: Bellville
country: South Africa
facility: GSK Investigational Site
city: Observatory
country: South Africa
facility: GSK Investigational Site
city: Panorama
country: South Africa
facility: GSK Investigational Site
city: Rondebosch
country: South Africa
facility: GSK Investigational Site
city: Tygerberg
country: South Africa
facility: GSK Investigational Site
city: Worcester
country: South Africa
facility: GSK Investigational Site
city: (Móstoles) Madrid
country: Spain
facility: GSK Investigational Site
city: Badalona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Getafe/Madrid
country: Spain
facility: GSK Investigational Site
city: L'Hospitalet de Llobregat
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Glasgow
country: United Kingdom
facility: GSK Investigational Site
state: Lanarkshire
city: Liverpool
country: United Kingdom
facility: GSK Investigational Site
state: Merseyside
city: Livingston
country: United Kingdom
facility: GSK Investigational Site
state: West Lothian
city: Bristol
country: United Kingdom
facility: GSK Investigational Site
city: Bristol
country: United Kingdom
facility: GSK Investigational Site
city: Cardiff
country: United Kingdom
facility: GSK Investigational Site
city: Leeds
country: United Kingdom
facility: GSK Investigational Site
city: Leicester
country: United Kingdom
facility: GSK Investigational Site
city: Leicester
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Oxford
country: United Kingdom
facility: GSK Investigational Site
city: Southampton
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Marty FM, Man CY, van der Horst C, Francois B, Garot D, Manez R, Thamlikitkul V, Lorente JA, Alvarez-Lerma F, Brealey D, Zhao HH, Weller S, Yates PJ, Peppercorn AF. Safety and pharmacokinetics of intravenous zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, single-arm, phase II study. J Infect Dis. 2014 Feb 15;209(4):542-50. doi: 10.1093/infdis/jit467. Epub 2013 Aug 27.