Safety Study to Assess IV Zanamivir for Treatment of Influenza Infection in Patients Who Are in Hospital
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.
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|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|
- 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 [ Time Frame: 33 days ] [ Designated as safety issue: Yes ]
- 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 [ Time Frame: 33 days ] [ Designated as safety issue: Yes ]
- 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. [ Time Frame: 33 days ] [ Designated as safety issue: Yes ]
- 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 [ Time Frame: 33 days ] [ Designated as safety issue: Yes ]
- 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) [ Time Frame: 33 days ] [ Designated as safety issue: No ]
- Time to no detectable viral RNA and to absence of cultivable virus in nasopharyngeal samples. [ Time Frame: 33 days ] [ Designated as safety issue: No ]
- Proportion of subjects who are negative by virus culture (and RT-PCR if available) in nasopharyngeal samples [ Time Frame: Day 3 to 33 days ] [ Designated as safety issue: No ]
- 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 [ Time Frame: 33 days ] [ Designated as safety issue: No ]
- Frequency of resistance emergence to zanamivir [ Time Frame: 33 days ] [ Designated as safety issue: No ]
- Mortality rate at Day 14 and Day 28 [ Time Frame: 33 days ] [ Designated as safety issue: Yes ]
- Incidence of complications of influenza and associated antibiotic use [ Time Frame: 33 days ] [ Designated as safety issue: Yes ]
- Ventilation status: modality, duration of supplemental oxygen and of mechanical ventilation [ Time Frame: 33 days ] [ Designated as safety issue: Yes ]
- 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 [ Time Frame: 33 days ] [ Designated as safety issue: Yes ]
- Length of total ICU stay and hospital stay as assessed from 1st day of dosing [ Time Frame: 33 days ] [ Designated as safety issue: No ]
- Level of activity: Time to return to pre-morbid functional status as assessed on a 3 point scale (bed rest, limited ambulation or unrestricted) [ Time Frame: 33 days ] [ Designated as safety issue: No ]
- 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 [ Time Frame: 33 days ] [ Designated as safety issue: No ]
- Time to sustained resolution of all vital signs (composite): afebrile status, normal respiratory status, normal heart rate, and normal blood pressure [ Time Frame: 33 days ] [ Designated as safety issue: No ]
|Study Start Date:||November 2009|
|Estimated Study Completion Date:||June 2013|
|Primary Completion Date:||September 2011 (Final data collection date for primary outcome measure)|
A single arm open-label design has been selected to achieve the primary objective of providing regulatory authorities with safety data on IV zanamivir in an expedited manner. This study design also facilitates the provision of safety data on a real-time basis, if necessary.
Drug: zanamivir aqueous solution
Zanamivir aqueous solution 10mg/mL is a clear, colorless, single use, sterile nonpreserved preparation containing 10mg of zanamivir in each millilitre, and made isotonic with sodium chloride. It is presented in 20mL clear glass vials closed with rubber stoppers. Each vial contains 200mg of zanamivir.
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.
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|Study Director:||GSK Clinical Trials||GlaxoSmithKline|