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A Study of Intravenous Zanamivir in the Treatment of Hospitalized Patients With Influenza Infection

Primary Purpose

Influenza, Human

Status

Completed

Phase

Phase 3

Locations

Japan

Study Type

Interventional

Intervention

Intravenous (IV) zanamivir

About this trial

This is an interventional treatment trial for Influenza, Human focused on measuring zanamivir, Seasonal Influenza, H1N1, intravenous, neuraminidase inhibitor, Pandemic, Relenza, Influenza B virus, Influenza A virus

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male or female aged greater than or equal to 16 years 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 use protocol specified methods of birth control while on study.
Subjects who have laboratory confirmed influenza as determined by a positive result in a rapid antigen test (RAT) for influenza A or influenza B, or a laboratory test for influenza including but not limited to influenza virus antigen test, virus culture or RT-PCR test.
Presence of fever [oral temperature of >=38 deg C, rectal, tympanic of >=38.5 deg C or axilla >=37.4 deg C] at Baseline. However, this requirement is waived if the subject has a history of fever within the 48 hours prior to Baseline and has been administered any antipyretic(s) in the 48 hours prior to Baseline.
Hospitalized subjects with symptomatic influenza as defined by ANY of the following.
1. Moderate to severe tachypnea (respiratory rate >=24/minute) OR
2. Moderate to severe dyspnea (unable to speak in full sentences) OR
3. Arterial oxygen saturation <95% on room air by trans-cutaneous method, or need for any supplemental oxygenation or ventilatory support [mechanical ventilation, bi-level positive airway pressure (bipap), continuous positive airway pressure (cpap)], or increase in oxygen supplementation requirement of >=2 litres for subjects with chronic oxygen dependency. For those subjects with a history of chronic hypoxia (without supplemental oxygen), an arterial oxygen saturation of at least 3% below the patient's historical baseline oxygen saturation will satisfy this criterion OR
4. Hemodynamic instability, defined as systolic blood pressure <90 mmHg or heart rate >100 beats per minute OR
5. Subject who became dehydrated and need whole-body management by hospitalization.
Onset of influenza symptoms within 6 days prior to study enrolment. Symptoms may include cough, dyspnea, sore throat, feverishness, myalgias, headache, nasal symptoms (rhinorrhea, congestion), fatigue, diarrhea, anorexia, nausea and vomiting.
Subjects/legally acceptable representative of unconscious adults willing and able to give written informed consent to participate in the study, and subjects willing to adhere to the procedures stated in the protocol.

Exclusion Criteria:

Subjects who, in the opinion of the investigator, are not likely to survive beyond 48 hours from Baseline.
Subjects who are considered to require concurrent therapy with another influenza antiviral medication.
Subjects who are known or suspected to be hypersensitive to any component of the study medications.
Subjects who require Extra Corporeal Membrane Oxygenation (ECMO) at Baseline (enrolled subject who subsequently require ECMO may continue in the study).
Liver toxicity criteria based on local laboratory results obtained at Baseline:
1. ALT or AST >=3xULN and bilirubin >=2xULN
2. ALT >=5xULN
Underlying chronic liver disease with evidence of severe liver impairment (Child-Pugh Class C).
History of severe cardiac disease or clinically significant arrhythmia (either on ECG or by history) which, in the opinion of the investigator or sub-investigator, will interfere with the safety of the individual subject.
Females who are pregnant (positive urine or serum pregnancy test at Baseline) or are breastfeeding.
QT criteria at Baseline as defined below:
1. QTcB or QTcF >480 msec
2. If a subject has bundle branch block then criteria is QTcB or QTcF >510 msec
Subject has participated in any study using an investigational drug during the previous 30 days.

Sites / Locations

GSK Investigational Site
GSK Investigational Site
GSK Investigational Site
GSK Investigational Site
GSK Investigational Site
GSK Investigational Site
GSK Investigational Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Intravenous (IV) zanamivir 600mg twice daily

Arm Description

600mg of IV zanamivir infusion twice daily

Outcomes

Primary Outcome Measures

Number of Participants With Any Adverse Event (AE), Drug-related AE, Grade 3 and Grade 4 AE, Grade 3 and 4 Drug-related AE , AE Leading to Discontinuation of Study Drug or From Study, Serious AE (SAE), Drug-related SAE, Fatal AE and Drug-related Fatal AE

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase >=3 x upper limit of normal (ULN), and total bilirubin >=2 x ULN or international normalised ratio >1.5. The grading of AEs and SAE's for 3/4 (3= severe, 4= potentially life threatening ) and its classification as potentially drug-related was done based on the investigator's judgment.

Number of Participants With Clinical Chemistry Parameters of Alanine Amino Transferase (ALT), Alkaline Phosphatase (ALP), Creatine Kinase and Aspartate Amino Transferase (AST) Outside the Normal Reference Range at Any Time During Treatment

The reference ranges for clinical chemistry parameters were ALT 5 to 45 international units per litre [IU/L]), ALP 100 to 325 IU/L, creatine kinase 60 to 270 IU/L and AST 10 to 40 IU/L. The baseline assessments were referred to assessments at Day 1. Assessments were done at Day 1, 3 and 5.

Number of Participants With Clinical Chemistry Parameters of Creatinine, Direct Bilirubin and Total Bilirubin Outside the Normal Reference Range at Any Time During Treatment

The reference ranges for clinical chemistry parameters were creatinine 41.548 - 69.836 micromole per litre (µmol/L), direct bilirubin 0 to 5.13 µmol/L and total bilirubin 3.42 to 20.52 µmol/L. The baseline assessments were referred to assessments at Day 1. Assessments were done at Day 1, 3 and 5.

Number of Participants With Clinical Chemistry Parameters of Calcium, Carbon Dioxide Content/ Bicarbonate, Chloride, Magnesium, Potassium, Sodium and Urea/ Blood Urea Nitrogen (BUN) Outside the Normal Reference Range at Any Time During Treatment

The reference ranges for clinical chemistry parameters were calcium 2.0958 to 2.5948 millimole per litre (mmol/L), carbon dioxide content/ bicarbonate 19.2 to 27.1 mmol/L, chloride 98 to 108 mmol/L, magnesium 0.7809 to 1.0275 mmol/L, potassium 3.5 to 5 mmol/L, sodium 137 to 147 mmol/L and urea/BUN 2.856 to 8.211 mmol/L. The baseline assessments were referred to assessments at Day 1. Assessments were done at Day 1, 3 and 5.

Number of Participants With Clinical Chemistry Parameters of Albumin and Total Protein Outside the Normal Reference Range at Any Time During Treatment

The reference ranges for clinical chemistry parameters were albumin 38 to 53 grams per liter (g/L) and total protein 67 to 83 g/L. The baseline assessments were referred to assessments at Day 1. Assessments were done at Day 1, 3 and 5.

Number of Participants With Hematology Parameters of Basophiles, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, White Blood Cell(WBC) Count, Hemoglobin and Hematocrit Outside the Normal Reference Range at Any Time During Treatment

The reference ranges for hematology parameters were basophils 0 to 2 percentage (%), eosinophils 0 to 8%, lymphocytes 18 to 49%, monocytes 2 to 10%, total neutrophils 40 to 75%, platelet count 140 to 340 giga cells per liter (GI/L), WBC count 3.3 to 9 GI/L, hemoglobin 135 to 175 g/L and haematocrit 0.397 to 0.524 ratio. The baseline assessments were referred to assessments at Day 1. Assessments were done at Day 1, 3, and 5.

Mean Change From Baseline in Albumin and Total Protein at the Indicated Time Points

Albumin and total protein were measured at Baseline , Day 3 and Day 5 during the treatment period. The baseline assessments were referred to assessments at Day 1. Change from Baseline was calculated as the value at the indicated time point minus the Baseline value.

Mean Change From Baseline in ALT, ALP, Creatine Kinase and AST at the Indicated Time Points

ALT, ALP, creatine kinase and AST were measured at Baseline, Day 3 and Day 5 during the treatment period. The baseline assessments were referred to assessments at Day 1. Change from Baseline was calculated as the value at the indicated time point minus the Baseline value.

Mean Change From Baseline in Creatinine, Direct Bilirubin and Total Bilirubin at the Indicated Time Points

Creatinine, direct bilirubin and total bilirubin were measured at Baseline, Day 3 and Day 5 during the treatment period. The baseline assessments were referred to assessments at Day 1. Change from Baseline was calculated as the value at the indicated time point minus the Baseline value.

Mean Change From Baseline in Sodium, Calcium, Potassium, Chloride, Magnesium, Carbon Dioxide Content/Bicarbonate and Urea/BUN at the Indicated Time Points

Calcium, potassium, chloride, magnesium, carbon dioxide content/bicarbonate, sodium and urea/BUN were measured at Baseline, Day 3 and Day 5 during the treatment period. The baseline assessments were referred to assessments at Day 1. Change from Baseline was calculated as the value at the indicated time point minus the Baseline value.

Mean Change From Baseline in Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes and Total Neutrophils at the Indicated Time Points

Percentages of basophils, eosinophils, lymphocytes, monocytes and total neutrophils were measured at Baseline, Day 3 and Day 5 during the treatment period. The baseline assessments were referred to assessments at Day 1. Change from Baseline was calculated as the value at the indicated time point minus the Baseline value.

Mean Change From Baseline in Counts of WBC and Platelets at the Indicated Time Points

WBC and platelet counts were measured at Baseline, Day 3 and Day 5 during the treatment period. The baseline assessments were referred to assessments at Day 1. Change from Baseline was calculated as the value at the indicated time point minus the Baseline value.

Mean Change From Baseline in Hemoglobin at the Indicated Time Points

Hemoglobin was measured at Baseline, Day 3 and Day 5 during the treatment period. The baseline assessments were referred to assessments at Day 1. Change from Baseline was calculated as the value at the indicated time point minus the Baseline value.

Mean Change Baseline in Hematocrit at the Indicated Time Points

Hematocrit was measured at Baseline, Day 3 and Day 5 during the treatment period. The baseline assessments were referred to assessments at Day 1. Change from Baseline was calculated as the value at the indicated time point minus the Baseline value.

Number of Participants With Toxicity Shifts From Baseline in Clinical Chemistry Over Period

The reference ranges for clinical chemistry parameters were ALT 5 to 45 IU/L, ALP 100 to 325 IU/L, creatine kinase 60 to 270 IU/L, AST 10 to 40 IU/L, creatinine 41.548 to 69.836 µmol/L, direct bilirubin 0 to 5.13 µmol/L, total bilirubin 3.42 to 20.52 µmol/L, calcium 2.0958 to 2.5948 mmol/L, CO2/ bicarbonate 19.2 to 27.1 mmol/L, chloride 98 to 108 mmol/L, magnesium 0.7809 to 1.0275 mmol/L, potassium 3.5 to 5 mmol/L, sodium 137 to 147 mmol/L and urea/ BUN 2.856 to 8.211 mmol/L. The baseline assessments were referred to assessments at Day 1. Number of participants with shifts between normal range (NR) high, within NR and NR low values in hematology parameters from baseline (Day 1) at Day 3 and Day 5 is reported.

Number of Participants With Toxicity Shifts From Baseline in Hematology Parameters Over Period

The reference ranges for hematology parameters were basophils 0 to 2%, eosinophils 0 to 8%, lymphocytes 18 to 49%, monocytes 2 to 10%, total neutrophils 40 to 75%, platelet count 140 to 340 GI/L, WBC count 3.3 to 9 GI/L, hemoglobin 135 to 175 g/L and haematocrit 0.397 to 0.524 ratio. The baseline assessments were referred to assessments at Day 1. Number of participants with shifts between NR high, within NR and NR low values in hematology parameters from baseline (Day 1) at Day 3 and Day 5 is reported.

Number of Participants of Treatment Emergent Toxicities in Clinical Chemistry and Hematology Over Period

The normal reference ranges for clinical chemistry and hematology parameters were ALT 5 to 45 IU/L, ALP 100 to 325 IU/L, creatine kinase 60 to 270 IU/L, AST 10 to 40 IU/L, creatinine 41.548 to 69.836 µmol/L, direct bilirubin 0 to 5.13 µmol/L, total bilirubin 3.42 to 20.52 µmol/L, calcium 2.0958 to 2.5948 mmol/L, CO2/ bicarbonate 19.2 to 27.1 mmol/L, chloride 98 to 108 mmol/L, magnesium 0.7809 to 1.0275 mmol/L, potassium 3.5 to 5 mmol/L, sodium 137 to 147 mmol/L, urea/ BUN 2.856 to 8.211 mmol/L, basophils 0 to 2%, eosinophils 0 to 8%, lymphocytes 18 to 49%, monocytes 2 to 10%, total neutrophils 40 to 75%, platelet count 140 to 340 GI/L, WBC count 3.3 to 9 GI/L, hemoglobin 135 to 175 g/L and haematocrit 0.397 to 0.524 ratio. Participants with treatment emergent toxicities for grade 3 (severe) and grade 4 (potentially life threatening) were assessed at Day 1, Day 3 and Day 5. Classification of the toxicities as potentially drug-related was done based on the investigator's judgment.

Mean Heart Rate (HR) of Participants Over Period

Vital sign of HR was assessed three times daily during the treatment period/hospitalization at Day 1, Day 2, Day 3, Day 4, Day 5 and Day 6. The baseline assessments were referred to assessments at Day 1. Maximum value in a day is reported where a 'day' is defined as a 24 h period (Treatment Day).

Mean Systolic and Diastolic Blood Pressure (SBP and DBP) of Participants Over Period

Vital signs of SBP and DBP were assessed three times daily during the treatment period/hospitalization at Day 1, Day 2, Day 3, Day 4, Day 5 and Day 6. The baseline assessments were referred to assessments at Day 1. Minimum value in a day for SBP is reported where a 'day' is defined as a 24 h period (Treatment Day). DBP is measured at the same time as minimum SBP.

Mean Oxygen Saturation (OS) of Participants Over Period

Vital signs of OS was assessed three times daily during the treatment period/hospitalization at Day 1, Day 2, Day 3, Day 4, Day 5 and Day 6. The baseline assessments were referred to assessments at Day 1. Minimum value in a day is reported, where a 'day' is defined as a 24 h period (Treatment Day).

Mean Respiratory Rate (RR) of Participants Over Period

Vital signs of RR was assessed three times daily during the treatment period/hospitalization at Day 1, Day 2, Day 3, Day 4, Day 5 and Day 6. The baseline assessments were referred to assessments at Day 1. Maximum value in a day is reported, where a 'day' was defined as a 24 h period (Treatment Day).

Mean Temperature of Participants Over Period

Vital signs of temperature was assessed three times daily during the treatment period/hospitalization at Day 1, Day 2, Day 3, Day 4, Day 5 and Day 6. The baseline assessments were referred to assessments at Day 1. Maximum value in a day is reported, where a'day' was defined as a 24 h period (Treatment Day).

Number of Participants With Abnormal Clinically Significant Electrocardiograph (ECG) Findings Over Period

12-lead ECG assessments were obtained at Baseline (Day 1) and Day 4 of the treatment period. On Baseline (Day 1), 2 baseline ECGs were obtained prior to study drug infusion. On Day 4, 2 ECGs were obtained, 1 ECG just prior to study drug infusion and 1 ECG at the end of infusion. Overall ECG findings were summarized with regard to visits at Day 1 (pre-dose [ECG 1 and ECG 2]) and Day 4 (pre-dose and 30-min post dose).

Percentage of Participants With Abnormal Clinically Significant ECG Findings Over Period

12-lead ECG assessments were obtained at Baseline (Day 1) and Day 4 of the treatment period. On Baseline (Day 1), 2 baseline ECGs were obtained. On Day 4, 2 ECGs were obtained, 1 ECG just prior to study drug infusion and 1 ECG at the end of infusion. Overall ECG findings were summarized at Day 1 (ECG 1 and ECG 2) and Day 4 (pre-dose and 30-min post dose).

Secondary Outcome Measures

Median Time to Absence of Fever, Improved Respiratory Status, Improved OS, Improved HR and Improved SBP Over Period

Absence of fever, improved respiratory status, OS, HR and SBP was defined according to clinical response criteria as: temperature, <= 36.6 degree C-axilla or <= 37.2 degree C-oral or <= 37.7 degree C-rectal and tympanic, without the use of antipyretics within 8 hour; OS of >= 95%; respiratory status of return to pre-morbid oxygen requirement (participants with chronic oxygen use) or need for supplemental oxygen (administered by any modality) to no need for supplemental oxygen or RR <=24 breaths/min without supplemental oxygen; HR <=100 beats/min; SBP of >=90 mmHg without inotropic support within 8 hour. For OS, participants with a history of chronic hypoxia (without supplemental oxygen) satisfied normalization criteria for OS if the value without supplemental oxygen was <=2% from participants historical OS and waiver for participants with a history of chronic supplemental oxygen requirement with baseline OS <95% with supplemental oxygen, recorded within 12 months prior to enrolment.

Median Time to Clinical Response Over Period

Clinical response was defined as resolution of at least 4 of the 5 vital signs within the respective resolution criteria of temperature <= 36.6 degree C-axilla or <= 37.2 degree C-oral or <= 37.7 degree C-rectal/ tympanic, without the use of antipyretics within 8 hour; OS of >= 95%; respiratory status of return to pre-morbid oxygen requirement (participants with chronic oxygen use) or need for supplemental oxygen (administered by any modality) to no need for supplemental oxygen or RR <= 24 breaths/min without supplemental oxygen; HR <=100 beats/min; SBP of >= 90 mmHg without inotropic support within 8 h, maintained for at least 24 hour, or hospital discharge, which ever occurred first. Participants discharged from hospital due to clinical improvement/resolution were considered to have met the clinical response endpoint at the time of hospital discharge and were not required to have documented resolution of at least 4 response criteria i.e. achieved success at the time of discharge.

Median Time to Return to Pre-morbid Level of Activity Over Period

Pre-morbid functional status was defined as the best functional status in the 4 weeks prior to enrolment and status at Baseline (Day 1). The participants were assessed on a 3-point scale by activity level (bed rest, limited ambulation or unrestricted) recorded in thee electronic case report form (eCRF). For participants who were unable to communicate their pre-morbid functional status, the information was requested from another close member of the household or close family member.

Number of Participants With and Without Use of Modality of Invasive, Non-invasive Ventilatory Support and Oxygen Supplementation Over Period

The non-invasive ventilator support includes modalities of machine-assisted: continuous positive airway pressure (CPAP) and bi-level positive airway pressure (BiPAP). The invasive ventilator support included modalities of machine-assisted: extra corporeal membrane oxygenation (ECMO) and endotracheal mechanical ventilation. Participants with and without use of modality of invasive, non-invasive ventilatory support and oxygen supplementation was assessed from Baseline (Day 1) to Day 33 (follow-up).

Median Duration of Use of Invasive and Non-invasive Ventilatory Support and Oxygen Supplementation Over Period

The non-invasive ventilator support includes modalities of machine-assisted: CPAP and BiPAP. The invasive ventilator support included modalities of machine-assisted: ECMO and endotracheal mechanical ventilation. Participants with use of modality of invasive, non-invasive ventilatory support and oxygen supplementation was assessed from Baseline (Day 1) to Day 33 (follow-up).

Median Duration of Intensive Care Unit (ICU) Stay for the Participants Over Period

The duration of ICU stay was assessed from the first day of dosing (Day 1) up to Day 33 (follow-up). Duration in ICU was captured from the eCRF. If the duration in ICU was missing, then the data was set to 0.

Median Duration of Hospital Stay for the Participants Over Period

The duration of hospital stay was assessed from the first day of dosing (Day 1) up to Day 33 (follow-up). The duration was calculated as duration in hospital = date/time of discharge - date/time of 1st day of dosing.

Mean 50% Inhibitory Concentration (IC50) for Phenotypes of Influenza for the Measure of Viral Susceptibility to Zanamivir at All Visits

IC50 value is defined as the concentration of zanamivir required to achieve half maximal inhibition of the influenza viral enzyme neuraminidase of influenza A and B to prevent the release and spread of influenza virus in the respiratory tract. Susceptibility analyses were performed on nasopharyngeal swabs collected on Baseline (Day 1) up to Day 33 (follow-up) depending on the extend of continuation of treatment and duration of hospitalization. Endotracheal aspirates were used in participants who were intubated. Data is categorized for participants with influenza A/H3N2 and influenza B.

Number of Participants With or Without Treatment Emergent Resistance or Suspected Treatment Emergent Resistance to Zanamivir Over Period

A total of 30 neuraminidase gene sequences (23 influenza A/H3N2, 5 influenza B and 2 negative) from 21 participants were obtained from 76 samples. There were no resistance associated neuraminidase mutations or mutations in the neuraminidase active site identified in viruses isolated during this study. Therefore the frequency of resistance emergence to zanamivir could not be determined.

Number of Participants of Clinical Symptoms of Influenza Over Period

Influenza symptoms were assessed at Baseline (pre-dose): the presence of the following symptoms were recorded: nasal symptoms (rhinorrhea, congestion), feverishness, cough, myalgias, fatigue, diarrhea, anorexia, dyspnea, headache, sore throat, nausea and vomiting. The investigator assessed and recorded influenza symptoms based on interview with the participants. In cases where participants were not able to communicate their symptoms, in participants ventilated and/or sedated, the investigator recorded those signs/symptoms as 'unable to assess'.

Median Duration of Clinical Symptoms of Influenza Over Period

Influenza symptoms were assessed at Baseline (pre-dose) and throughout the study period as presence of the following symptoms were recorded: nasal symptoms (rhinorrhea, congestion), feverishness, cough, myalgias, fatigue, diarrhea, anorexia, dyspnea, headache, sore throat, nausea and vomiting. The investigator assessed and recorded influenza symptoms based on interview with the participants. In cases where participants were not able to communicate their symptoms, in participants ventilated and/or sedated, the investigator recorded those signs/symptoms as 'unable to assess'.

Number of Participants With Complications of Influenza and Associated Use of Antibiotics Over Period

The details of complications of influenza like bacterial pneumonia, pneumothorax, pleural effusion, acute respiratory distress syndrome (ARDS), myositis, encephalitis, myocarditis and associated antibiotic use were assessed from Baseline (Day 1) to Day 33 (follow-up). Participants with complications of influenza, with associated use of antibiotics as " associated antibiotic use yes" and without associated use of antibiotics as "associated antibiotic use no" were categorized.

Median Time to Virologic Improvement Over Period

Virologic improvement was defined as a 2 log drop in viral load or sustained undetectable viral ribonucleic acid (RNA), on 2 successive occasions as measured by quantitative reverse transcriptase - polymerase chain reaction (RT-PCR) from nasopharyngeal samples. Assessment was done from Baseline (Day 1) up to Day 33 (follow-up).

Percentage of Participants With Undetectable Viral RNA and Absence Cultivable Virus From Samples Obtained From Nasopharyngeal Samples Over Period

Quantitative RT-PCR and quantitative viral culture was carried out on nasopharyngeal swabs collected from Baseline (Day 1) up to Day 33 (follow-up) depending on the extend of continuation of treatment and duration of hospitalization of the participants. Undetectable RNA concentrations were below the level of quantification.

Percentage of Participants With Undetectable Viral RNA and Absence of Cultivable Virus in Lower Respiratory Samples Over Period

Quantitative RT-PCR and quantitative viral culture was carried out on lower respiratory samples (endotracheal aspirates) collected on Baseline (Day 1) up to Day 33 (follow-up) depending on the extend of continuation of treatment and duration of hospitalization. Endotracheal aspirates were used in participants who were intubated. Undetectable RNA concentrations were below the level of quantification.

Median Time to no Detectable Viral RNA by Quantitative RT-PCR and Viral Culture From Nasopharyngeal Samples Over Period

Quantitative RT-PCR and quantitative viral culture was carried out on nasopharyngeal swabs collected on Baseline (Day 1) up to Day 33 (follow-up) depending on the extend of continuation of treatment and duration of hospitalization.

Mean Change From Baseline in Quantitative Viral Load Measured by RT-PCR From Nasopharyngeal Swabs Positive at Baseline Over Period

Quantitative RT-PCR was carried out on nasopharyngeal swabs collected on Day 1 up to Day 33 (last day) depending on the extend of continuation of treatment and duration of hospitalization. The baseline assessments were referred to assessments at Day 1. Change from Baseline was calculated as the value at the indicated time point minus the Baseline value. Analysis was done for participants with positive Influenza A RNA and Influenza B RNA. Data is presented for Day 3, Day 5 and last day.

Mean Change From Baseline in Quantitative Viral Load Measured by Viral Culture From Nasopharyngeal Swabs Over Period

Quantitative viral culture as 50 % tissue culture infectious dose (TCID50) defined as median tissue culture infective dose is that amount of a pathogenic agent that produces pathological change in 50% of cell cultures inoculated. It was carried out on nasopharyngeal swabs collected on Day 1 up to Day 33 (last day) depending on the extend of continuation of treatment and duration of hospitalization. The baseline assessments were referred to assessments at Day 1. Change from Baseline was calculated as the value at the indicated time point minus the Baseline value. Any undetectable viral load values were calculated as x.x Log10 TCID50: x.x Log10 (1.5 or 7.5 was the lower or upper limit of quantification in TCID50). Data is presented for Day 3, Day 5 and last day.

Full Information

NCT ID

NCT01527110

First Posted

December 8, 2011

Last Updated

February 20, 2018

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT01527110

Brief Title

A Study of Intravenous Zanamivir in the Treatment of Hospitalized Patients With Influenza Infection

Official Title

An Open-label, Multi-centre, Single Arm Study to Evaluate the Safety and Efficacy of Intravenous Zanamivir in the Treatment of Hospitalized Patients With Confirmed Influenza Infection (NAI115215)

Study Type

Interventional

2. Study Status

Record Verification Date

July 2017

Overall Recruitment Status

Completed

Study Start Date

January 1, 2012 (undefined)

Primary Completion Date

March 1, 2013 (Actual)

Study Completion Date

March 29, 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

This study will be an open-label, multi-center, single arm study to evaluate the safety and efficacy of IV zanamivir 600mg twice daily for 5 days in hospitalized subjects with laboratory confirmed influenza infection.

Detailed Description

Adult subjects and adolescent subjects (≥50 kg) with normal renal function will receive 600mg per dose. Subjects with renal impairment will receive an adjusted dose based on calculated creatinine clearance. 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. 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. For subjects who have been discharged from hospital, the Post-Treatment +2, +5, +9 and +16 Days Assessments can be made by telephone contact.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Influenza, Human

Keywords

zanamivir, Seasonal Influenza, H1N1, intravenous, neuraminidase inhibitor, Pandemic, Relenza, Influenza B virus, Influenza A virus

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

21 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Intravenous (IV) zanamivir 600mg twice daily

Arm Type

Experimental

Arm Description

600mg of IV zanamivir infusion twice daily

Intervention Type

Drug

Intervention Name(s)

Intravenous (IV) zanamivir

Intervention Description

Zanamivir aqueous solution 10mg/mL, 600mg of IV zanamivir infusion twice daily for 5 days

Primary Outcome Measure Information:

Title

Description

Time Frame

Start of treatment (Day 1) up to follow-up (Day 33)

Title

Description

Time Frame

Baseline (Day 1) to Day 5

Title

Number of Participants With Clinical Chemistry Parameters of Creatinine, Direct Bilirubin and Total Bilirubin Outside the Normal Reference Range at Any Time During Treatment

Description

Time Frame

Baseline (Day 1) to Day 5

Title

Description

Time Frame

Baseline (Day 1) to Day 5

Title

Number of Participants With Clinical Chemistry Parameters of Albumin and Total Protein Outside the Normal Reference Range at Any Time During Treatment

Description

Time Frame

Baseline (Day 1) to Day 5

Title

Description

Time Frame

Baseline (Day 1) to Day 5

Title

Mean Change From Baseline in Albumin and Total Protein at the Indicated Time Points

Description

Time Frame

Baseline (Day 1), Day 3 and Day 5

Title

Mean Change From Baseline in ALT, ALP, Creatine Kinase and AST at the Indicated Time Points

Description

Time Frame

Baseline (Day 1), Day 3 and Day 5

Title

Mean Change From Baseline in Creatinine, Direct Bilirubin and Total Bilirubin at the Indicated Time Points

Description

Time Frame

Baseline (Day 1), Day 3 and Day 5

Title

Mean Change From Baseline in Sodium, Calcium, Potassium, Chloride, Magnesium, Carbon Dioxide Content/Bicarbonate and Urea/BUN at the Indicated Time Points

Description

Time Frame

Baseline (Day 1), Day 3 and Day 5

Title

Mean Change From Baseline in Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes and Total Neutrophils at the Indicated Time Points

Description

Time Frame

Baseline, Day 3 and Day 5

Title

Mean Change From Baseline in Counts of WBC and Platelets at the Indicated Time Points

Description

Time Frame

Baseline (Day 1), Day 3 and Day 5

Title

Mean Change From Baseline in Hemoglobin at the Indicated Time Points

Description

Time Frame

Baseline (Day 1), Day 3 and Day 5

Title

Mean Change Baseline in Hematocrit at the Indicated Time Points

Description

Time Frame

Baseline (Day 1), Day 3 and Day 5

Title

Number of Participants With Toxicity Shifts From Baseline in Clinical Chemistry Over Period

Description

Time Frame

Baseline (Day 1), Day 3 and Day 5

Title

Number of Participants With Toxicity Shifts From Baseline in Hematology Parameters Over Period

Description

Time Frame

Baseline (Day 1), Day 3 and Day 5

Title

Number of Participants of Treatment Emergent Toxicities in Clinical Chemistry and Hematology Over Period

Description

Time Frame

Day 1, Day 3 and Day 5

Title

Mean Heart Rate (HR) of Participants Over Period

Description

Time Frame

Baeline (Day 1) to Day 6

Title

Mean Systolic and Diastolic Blood Pressure (SBP and DBP) of Participants Over Period

Description

Time Frame

Baseline (Day 1) to Day 6

Title

Mean Oxygen Saturation (OS) of Participants Over Period

Description

Time Frame

Baseline (Day 1) to Day 6

Title

Mean Respiratory Rate (RR) of Participants Over Period

Description

Time Frame

Baseline (Day 1) to Day 6

Title

Mean Temperature of Participants Over Period

Description

Time Frame

Baseline (Day 1) to Day 6

Title

Number of Participants With Abnormal Clinically Significant Electrocardiograph (ECG) Findings Over Period

Description

Time Frame

Baseline (Day 1, pre-dose) and Day 4

Title

Percentage of Participants With Abnormal Clinically Significant ECG Findings Over Period

Description

Time Frame

Baseline ( pre-dose Day 1) and Day 4

Secondary Outcome Measure Information:

Title

Median Time to Absence of Fever, Improved Respiratory Status, Improved OS, Improved HR and Improved SBP Over Period

Description

Time Frame