Safety Study to Assess IV Zanamivir for Treatment of Influenza Infection in Patients Who Are in Hospital

Influenza, Human Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01014988
• Other study ID #: 113678
• Status: Completed
• Phase: Phase 2
• First received: November 16, 2009
• Last updated: August 12, 2016
• Start date: November 2009
• Est. completion date: February 2015

Study information

• Verified date: August 2016
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencySpain: Bernat SoriaRussia: Russian Ministry of HealthThailand: Ministry of Public HealthCanada: Health CanadaFrance: Agence Française de Sécurité Sanitaire des Produits de SantéUnited States: Institutional Review BoardGermany: Federal Institute for Drugs and Medical DevicesUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 202
• Est. completion date: February 2015
• Est. primary completion date: February 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Months and older

Eligibility

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.

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Influenza, Human

Intervention

Drug:
• zanamivir aqueous solution
Zanamivir aqueous solution 10mg/mL is a clear, colorless, single use, sterile non-preserved preparation containing 10mg of zanamivir in each milliliter, and made isotonic with sodium chloride. It is presented in 20mL clear glass vials closed with rubber stoppers. Each vial contains 200mg of zanamivir.

Locations

Country	Name	City	State
Australia	GSK Investigational Site	Adelaide	South Australia
Australia	GSK Investigational Site	Bedford Park	South Australia
Australia	GSK Investigational Site	Chermside	Queensland
Australia	GSK Investigational Site	Garran	Australian Capital Territory
Australia	GSK Investigational Site	Heidelberg	Victoria
Australia	GSK Investigational Site	Herston	Queensland
Australia	GSK Investigational Site	Perth	Western Australia
Australia	GSK Investigational Site	Subiaco	Western Australia
Brazil	GSK Investigational Site	Rio de Janeiro
Brazil	GSK Investigational Site	Sao Paulo	São Paulo
Canada	GSK Investigational Site	Chicoutimi	Quebec
Canada	GSK Investigational Site	Halifax	Nova Scotia
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Quebec
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Winnipeg	Manitoba
France	GSK Investigational Site	Bron cedex
France	GSK Investigational Site	Grenoble cedex 9
France	GSK Investigational Site	Limoges cedex
France	GSK Investigational Site	Nancy cedex
France	GSK Investigational Site	Nice
France	GSK Investigational Site	Nîmes cedex 9
France	GSK Investigational Site	Orléans cedex 2
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Paris cedex 14
France	GSK Investigational Site	Tours cedex 9
Hong Kong	GSK Investigational Site	Shatin
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Hokkaido
Japan	GSK Investigational Site	Kanagawa
Japan	GSK Investigational Site	Osaka
Japan	GSK Investigational Site	Osaka
Japan	GSK Investigational Site	Yamanashi
Norway	GSK Investigational Site	Bergen
Norway	GSK Investigational Site	Trondheim
Russian Federation	GSK Investigational Site	Ekaterinburg
Russian Federation	GSK Investigational Site	Smolensk
South Africa	GSK Investigational Site	Bellville
South Africa	GSK Investigational Site	Middelburg	Mpumalanga
South Africa	GSK Investigational Site	Observatory
South Africa	GSK Investigational Site	Panorama
South Africa	GSK Investigational Site	Rondebosch
South Africa	GSK Investigational Site	Tygerberg
South Africa	GSK Investigational Site	Worcester
Spain	GSK Investigational Site	(Móstoles) Madrid
Spain	GSK Investigational Site	Badalona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Getafe/Madrid
Spain	GSK Investigational Site	L'Hospitalet de Llobregat
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Thailand	GSK Investigational Site	Bangkok
Thailand	GSK Investigational Site	Bangkok
United Kingdom	GSK Investigational Site	Bristol
United Kingdom	GSK Investigational Site	Bristol
United Kingdom	GSK Investigational Site	Cardiff
United Kingdom	GSK Investigational Site	Glasgow	Lanarkshire
United Kingdom	GSK Investigational Site	Leeds
United Kingdom	GSK Investigational Site	Leicester
United Kingdom	GSK Investigational Site	Leicester
United Kingdom	GSK Investigational Site	Liverpool	Merseyside
United Kingdom	GSK Investigational Site	Livingston	West Lothian
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Oxford
United Kingdom	GSK Investigational Site	Southampton
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Butte	Montana
United States	GSK Investigational Site	Camden	New Jersey
United States	GSK Investigational Site	Chapel Hill	North Carolina
United States	GSK Investigational Site	Charlotte	North Carolina
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Decatur	Georgia
United States	GSK Investigational Site	Fort Worth	Texas
United States	GSK Investigational Site	Gainesville	Florida
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Indianapolis	Indiana
United States	GSK Investigational Site	Kansas City	Missouri
United States	GSK Investigational Site	Little Rock	Arkansas
United States	GSK Investigational Site	Louisville	Kentucky
United States	GSK Investigational Site	Memphis	Tennessee
United States	GSK Investigational Site	Memphis	Tennessee
United States	GSK Investigational Site	Milwaukee	Wisconsin
United States	GSK Investigational Site	New Hyde Park	New York
United States	GSK Investigational Site	New Orleans	Louisiana
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Phoenix	Arizona
United States	GSK Investigational Site	Pittsburgh	Pennsylvania
United States	GSK Investigational Site	Portland	Oregon
United States	GSK Investigational Site	Richmond	Virginia
United States	GSK Investigational Site	Salt Lake City	Utah
United States	GSK Investigational Site	San Diego	California
United States	GSK Investigational Site	St. Louis	Missouri
United States	GSK Investigational Site	St. Paul	Minnesota
United States	GSK Investigational Site	Stamford	Connecticut
United States	GSK Investigational Site	Tampa	Florida
United States	GSK Investigational Site	Toledo	Ohio
United States	GSK Investigational Site	Topeka	Kansas
United States	GSK Investigational Site	Washington	District of Columbia
United States	GSK Investigational Site	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  France,  Hong Kong,  Japan,  Norway,  Russian Federation,  South Africa,  Spain,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of AEs, including AE considered to be related to study treatment, grade 3/4 or severe AEs and those treatment related, AEs leading to discontinuation of study drug or study, SAEs, treatment related SAEs, fatal events		33 days	Yes
Primary	Clinical chemistry and hematology data values outside the normal range, Clinical laboratory data summarized based on changes from baseline and toxicity shifts from baseline, treatment emergent toxicities		33 days	Yes
Primary	Heart rate, blood pressure, oxygen saturation, respiration rate and temperature will be summarized by visit, change from baseline of the vital signs will be summarized.		33 days	Yes
Primary	Number and percentage of subjects who had abnormal and/or clinically significant ECG findings. If available, ECG interval data and change from baseline, QTc interval will be calculated		33 days	Yes
Secondary	Change in quantitative viral load over time and change from baseline measured from nasopharyngeal swab samples, as determined by quantitative virus culture (and retrospectively by RT-PCR, if available)		33 days	No
Secondary	Time to no detectable viral RNA and to absence of cultivable virus in nasopharyngeal samples.		33 days	No
Secondary	Proportion of subjects who are negative by virus culture (and RT-PCR if available) in nasopharyngeal samples		Day 3 to 33 days	No
Secondary	Viral susceptibility to zanamivir at baseline, and if virus present, at subsequent timepoints during the study, as assessed by NA sequence analysis and NA enzyme inhibition assay		33 days	No
Secondary	Frequency of resistance emergence to zanamivir		33 days	No
Secondary	Mortality rate at Day 14 and Day 28		33 days	Yes
Secondary	Incidence of complications of influenza and associated antibiotic use		33 days	Yes
Secondary	Ventilation status: modality, duration of supplemental oxygen and of mechanical ventilation		33 days	Yes
Secondary	Time to resolution of individual vital signs: afebrile status, return to normal respiratory status, return to normal heart rate, and time to return to normal systolic blood pressure		33 days	Yes
Secondary	Length of total ICU stay and hospital stay as assessed from 1st day of dosing		33 days	No
Secondary	Level of activity: Time to return to pre-morbid functional status as assessed on a 3 point scale (bed rest, limited ambulation or unrestricted)		33 days	No
Secondary	Time to virologic improvement, defined as a 2-log drop in viral load or undetectable viral RNA as measured by quantitative RT-PCR from nasopharyngeal samples		33 days	No
Secondary	Time to sustained resolution of all vital signs (composite): afebrile status, normal respiratory status, normal heart rate, and normal blood pressure		33 days	No

External Links

•   Centers For Disease Control and Prevention 2009 H1N1 flu information
•   Centers For Disease Control and Prevention seasonal flu information
•   FDA information on Influenza (Flu) antiviral drugs and related information