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A Study of Intravenous Zanamivir Versus Oral Oseltamivir in Adults and Adolescents Hospitalized With Influenza (ZORO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01231620
Recruitment Status : Completed
First Posted : November 1, 2010
Results First Posted : November 20, 2017
Last Update Posted : October 15, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
The purpose of this study is to test the safety and efficacy of zanamivir given intravenously and how well it works at two different doses in hospitalized adolescents and adults with flu. Zanamivir will be compared with oseltamivir, which is used for treating flu.

Condition or disease Intervention/treatment Phase
Influenza, Human Drug: Zanamivir Drug: Placebo to match zanamivir Drug: Oseltamivir Drug: Placebo to match oseltamivir Phase 3

Detailed Description:
The recent influenza pandemic has highlighted the need for alternative formulations for anti-influenza therapies. This will be an international Phase III, double-blind, double-dummy, 3-arm study to evaluate the efficacy, antiviral activity and safety of IV zanamivir 600 mg twice daily compared to oral oseltamivir 75 mg twice daily, and 600 mg IV zanamivir twice daily compared to 300 mg IV zanamivir for 5 days in hospitalized subjects with laboratory confirmed or suspected influenza infection. For a given subject, the initial 5-day treatment course may be extended for up to 5 additional days if clinical symptoms or patient characteristics as assessed by the investigator warrant further treatment. Alternatively, if the investigator considers that a subject is failing to improve clinically on their randomized treatment, the investigator can choose to initiate the switch/rescue option (600 mg IV zanamivir twice daily) on any day from Day 6 through Day 10 for up to an additional 5 days of treatment. On switching treatments, subjects complete a maximum of 14 days of treatment and are followed-up to Post-Treatment +28 Days.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 626 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase III International, Randomized, Double-blind, Double-dummy Study to Evaluate the Efficacy and Safety of 300 mg or 600 mg of Intravenous Zanamivir Twice Daily Compared to 75 mg of Oral Oseltamivir Twice Daily in the Treatment of Hospitalized Adults and Adolescents With Influenza
Actual Study Start Date : January 15, 2011
Actual Primary Completion Date : March 18, 2015
Actual Study Completion Date : March 18, 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Flu Flu Shot

Arm Intervention/treatment
Experimental: Intravenous (IV) Zanamivir 300mg Twice Daily
300mg of IV zanamivir infusion twice daily plus oral oseltamivir placebo twice daily
Drug: Zanamivir
Zanamivir aqueous solution, 10 mg/mL, will be provided as a single use, sterile clear, colorless preparation in 20 mL clear glass vials.
Other Name: Relenza

Drug: Placebo to match oseltamivir
Placebo to match oral oseltamivir will be provided as capsules with a common excipient of appropriate quality.

Experimental: Intravenous (IV) Zanamivir 600mg Twice Daily
600mg of IV zanamivir infusion twice daily plus oral oseltamivir placebo twice daily
Drug: Zanamivir
Zanamivir aqueous solution, 10 mg/mL, will be provided as a single use, sterile clear, colorless preparation in 20 mL clear glass vials.
Other Name: Relenza

Drug: Placebo to match oseltamivir
Placebo to match oral oseltamivir will be provided as capsules with a common excipient of appropriate quality.

Active Comparator: Oral Oseltamivir 75mg Twice Daily
75mg oral oseltamivir twice daily plus intravenous placebo zanamivir twice daily
Drug: Placebo to match zanamivir
Placebo to match IV zanamivir will be provided as a normal saline solution of a matched volume.

Drug: Oseltamivir
Oseltamivir will be provided as over-encapsulated 75 mg capsules.
Other Name: Tamiflu




Primary Outcome Measures :
  1. Time to Clinical Response (TTCR) in Participants With Confirmed Influenza [ Time Frame: Up to 42 days ]
    Clinical response is defined as the resolution of at least 4 of the 5 vital signs (temperature, oxygen saturation, respiratory status, heart rate, systolic blood pressure) within the respective resolution criteria, maintained for at least 24 hours, or hospital discharge, whichever occurred first. This analysis was performed for Influenza positive population, for those with symptom onset less than or equal to (<=) 4 days, and for those on mechanical (mech) ventilation or in intensive care unit (ICU). 99 days is censored time for the participants who did not achieve TTCR.


Secondary Outcome Measures :
  1. Percentage of Participants With Respiratory Improvement [ Time Frame: Up to 42 days ]
    Respiratory Status (RS) is a component of TTCR. Response criteria included the return to the pre-morbid oxygen requirement (participants with chronic oxygen use), a need for supplemental oxygen (administered by any modality: ventilator, non-invasive ventilation, facemask, facetent, nasal canula, etc.) to no need for supplemental oxygen, or a respiratory rate of =<24 breaths/minute (without supplemental oxygen). Data are presented as the percentage of participants achieving respiratory improvement.

  2. Number of Participants With All Cause and Attributable Mortality at Day 14, at Day 28, and at the End of Study Visit [ Time Frame: On or before Day 14, Day 28, End of Study Visit (assessed up to 42 days) ]
    The number of participants who died on or before Day 14, Day 28, and the End of Study Visit were summarized.

  3. Change From Baseline in the Katz Activities of Daily Living (ADL) Score and Each ADL Activity Score [ Time Frame: Baseline (Day 1) and up to 42 days ]
    The Katz ADL scores were collected for bathing, dressing, toileting, transferring, continence, and feeding activities and were assessed once daily during the treatment period/hospitalization and once at each post-treatment Clinic Visit. For the six individual activities, a score of 1 indicates independence, and a score of 0 indicates dependence. The total score is generated by adding the scores of all six activities. A total score of 6 indicates that the participant was independent; a total score of 0 indicates that the participant was very dependent. Baseline is defined as the pre-dose value collected on Study Day 1. Change from Baseline is defined as the difference at each time point (Day 5/6, and Day 10/11, and last day S/R if treatment was extended beyond 5 days) and the end of the study (post-treatment [PT] +28 Days) compared to Baseline.

  4. Median Time to Return to Pre-morbid Functional Status as Measured by the Katz ADL Score and Each ADL Activity Score [ Time Frame: Up to 42 days ]
    Pre-morbid functional status is defined as the best functional status in the 4 weeks prior to enrolment. Median time to return to pre-morbid functional status was assessed via the Katz ADL score (bathing, dressing, toileting, transferring, continence, and feeding activities). For the six individual activities, a score of 1 indicates independence, and a score of 0 indicates dependence. The total score is generated by adding the scores of all six activities. A total score of 6 indicates that the participant was independent; a total score of 0 indicates that the participant was very dependent.

  5. Number of Participants Who Returned to Their Pre-morbid Functional Status as Assessed Per the Katz ADL Score and Each ADL Activity Score at the End of the Study [ Time Frame: Up to 42 days ]
    Pre-morbid functional status is defined as the best functional status in the 4 weeks prior to enrolment. The number of participants who returned to their pre-morbid functional status at the end of the study assessed per the Katz ADL score (bathing, dressing, toileting, transferring, continence and feeding activities) is summarized.

  6. Median Time to Return to the Pre-morbid Level of Activity as Measured by the 3-point Scale [ Time Frame: Up to 42 days ]
    Median time to return to pre-morbid level of activity was assessed once daily during treatment/hospitalization and once at each post-treatment assessment and was measured using the 3- point scale (bed rest, limited ambulation, or unrestricted).

  7. Number of Participants With the Indicated Clinical Symptoms of Influenza [ Time Frame: Up to 42 days ]
    Influenza clinical symptoms included nasal symptoms (rhinorrhea, congestion), feverishness, cough, myalgias, fatigue, diarrhea, anorexia, dyspnea, headache, sore throat, nausea, and vomiting. Influenza symptoms were assessed once daily during inpatient hospitalization and once at each post-treatment assessment.

  8. Median Time of Duration of Clinical Symptoms of Influenza [ Time Frame: Up to 42 days ]
    Influenza clinical symptoms included nasal symptoms (rhinorrhea, congestion), feverishness, cough, myalgias, fatigue, diarrhea, anorexia, dyspnea, headache, sore throat, nausea, and vomiting. Influenza symptoms were assessed once daily during inpatient/hospitalization and once at each post-treatment assessment.

  9. Number of Participants With Complications of Influenza and Associated Antibiotic Use [ Time Frame: Up to 42 days ]
    The number of participants with complications of influenza and associated antibiotic use were summarized

  10. Number of Participants With the Indicated Ventilation Status: Modality of Invasive and Non-invasive Ventilator Support and Oxygen Supplementation [ Time Frame: Up to 42 days ]
    Ventilation status was assessed three times daily during the treatment period/hospitalization. Ventilation status was assessed once daily during inpatient/hospitization and once at each post-treatment clinic visit. The number of participants reported for machine-assisted: extracorporeal membrane oxygenation (ECMO), endotracheal mechanical ventilation, and supplemental oxygen delivery (SOD), no supplemental oxygen (O2) or ventilation support, Respiratory support at "any time (AT) on study" and at Baseline (Day 1) are summarized. Data for the "any time (AT) on study" time point was reported.

  11. Median Time of Duration of Invasive and Non-invasive Ventilator Support and Oxygen Supplementation [ Time Frame: Baseline (Day 1) and up to 42 days ]
    Ventilation status was assessed three times daily during the treatment period/hospitalization. Ventilation status was assessed once daily during inpatient/hospitalization and once at each post-treatment clinic visit.

  12. Median Time of Duration of Hospitalization and Intensive Care Unit (ICU) Stay [ Time Frame: Day 1 to the end of the study (assessed up to 42 days) ]
    Hospital duration and ICU duration was assessed from the first day of dosing. Hospital duration was calculated as the discharge date minus the admission date + 1. Hospital duration while on study was the earlier of discharge, completion, or withdrawal minus the later of the admission date or the study start date + 1. ICU duration-Modified was calculated as the original ICU duration minus ICU days prior to Study Day 1.

  13. Median Time to the Absence of Fever and Improved Respiratory Status, Oxygen Saturation, Heart Rate, and Systolic Blood Pressure [ Time Frame: Baseline (Day 1) and up to 42 days ]
    The absence of fever is defined as a non-axillary temperature recording <=36.6 degrees Celsius axillary, <= 37.2 degrees Celsius oral or <= 37.7 degrees Celsius core. Respiratory Status (RS) response criteria included the return to the pre-morbid oxygen requirement (participants with chronic oxygen use), or the need for supplemental oxygen (administered by any modality: ventilator, non-invasive ventilation, facemask, facetent, nasal canula, etc.) to no need for supplemental oxygen, or a respiratory rate =<24 breaths/minute (without supplemental oxygen). Oxygen saturation response criteria: >=95% (without supplemental oxygen). Heart rate response criteria: =<100 beats/minute. Systolic blood pressure response criteria: >=90 millimeters of mercury. Vital signs were assessed three times daily during the treatment period/hospitalization. Vital signs were assessed once daily during inpatient/hospitization and once at each post-treatment clinic visit.

  14. Median Time to Virologic Improvement [ Time Frame: Baseline (Day 1) and up to 42 days ]
    Virologic improvement is defined as a 2 log drop in viral load or sustained undetectable viral ribonucleic acid (RNA) (on two successive occasions) as measured by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) from nasopharyngeal samples. Nasopharyngeal swabs were collected daily from Baseline through Day 5. If randomized treatment was continued beyond Day 5, samples were taken on Treatment Days 6, 8, 10 and on the last day of randomized treatment. For participants who utilized the Switch (S)/Rescue (R) option, samples were taken on S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6, whichever was the last day of S/R treatment. Nasopharyngeal swabs were taken if the participant was symptomatic and continued to be hospitalized on the Post-Treatment +2, +5, +9, +16, and +28 day assessment.

  15. Change From Baseline in Quantitative Virus Culture From Nasopharyngeal Swabs Positive at Baseline [ Time Frame: Baseline (Day 1), Day 3, Day 5, Day 8, Day 10, Day 11 and/or last day of randomized treatment, if randomized treatment was extended beyond 5 days, and S/R Day 5/6 (up to Day 14) if applicable ]
    Nasopharyngeal swabs were collected daily from Baseline through Day 5. If randomized treatment was continued beyond Day 5, samples were taken on Treatment Day 6, Day 8, Day 10, Day 11, and the last day of randomized treatment. For participants who utilized the S/R option, samples were taken on S/R Day1, S/R Day3, S/R Day5, or S/R Day6, whichever was the last day of S/R treatment. Samples were taken if the participant was symptomatic and continued to be hospitalized on the Post-Treatment +2, +5, +9, +16 and +28Day assessment. Viral load was measured by Quantitative Virus Culture, log10 50% Tissue Culture Infectious Dose (TCID50)/milliliter (mL). Baseline is defined as the pre-dose value collected on Study Day 1. Change from Baseline was calculated as the post-Baseline value minus Baseline value .

  16. Change From Baseline Viral Load (Influenza A or B) by qPCR From Nasopharyngeal Swabs Positive at Baseline [ Time Frame: Baseline (Day 1), Day 3, Day 5, Day 8, Day 10, Day 11 and/or last day of randomized treatment, if randomized treatment was extended beyond 5 days, and S/R Day 5/6 (up to Day 14) if applicable ]
    Nasopharyngeal swabs were collected daily from Baseline through Day 5. If randomized treatment was continued beyond Day 5, samples were taken on Treatment Day 6, Day 8, Day 10, Day 11, and the last day of randomized treatment. For participants who utilized the S/R option, samples were taken on S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6, whichever was the last day of S/R treatment. Samples were taken if the participant was symptomatic and continued to be hospitalized on the post-treatment +2, +5, +9, +16 and +28 day assessment. Viral load as measured by PCR. Baseline is defined as the pre-dose value collected on Study Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  17. Number of Participants With no Detectable Viral RNA and the Absence of Cultivable Virus in Lower Respiratory Samples (Bronchoalveolar Lavage Sample [BAL], Endotracheal Aspirate) [ Time Frame: Baseline (Day 1) and up to 42 days ]
    Lower respiratory samples included BAL and endotracheal aspirates. Endotracheal aspirates were requested in participants (par.) who were intubated. Upper (nasopharyngeal swabs) and lower (Endotracheal aspirates, bronchoalveolar lavage samples) respiratory samples were collected daily from Baseline/Day 1 through Day 5 and Day 6 (if the last day of randomized treatment [trt]). Endotracheal aspirates were collected in participants who were intubated. If trt was continued beyond Day 5, additional samples were taken on Trt Day 6, Day 8, Day 10, and/or the day of the last dose of randomized trt, if applicable, and S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6 if the last day of S/R trt. If the par. was symptomatic and hospitalized, samples were taken on the Post-Trt +2, +5, +9, +16 assessment days, and at the Post-Trt [PT]+28 Day assessment. Assessment of samples was done by quantitative RT-PCR and viral culture.

  18. Median Time to no Detectable Viral RNA and the Absence of Cultivable Virus in Any Obtained Sample (Upper and Lower Respiratory Samples) [ Time Frame: Baseline (Day 1) and up to 42 days ]
    Upper (nasopharyngeal swabs) and lower (Endotracheal aspirates, bronchoalveolar lavage samples, where available) respiratory samples were collected daily from Baseline/Day 1 through Day 5 and Day 6 (if the last day of randomized treatment). Endotracheal aspirates were collected in participants who were intubated. If treatment was continued beyond Day 5, additional samples were taken on Treatment Day 6, Day 8, Day 10, and/or the day of the last dose of randomized treatment, if applicable, and S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6 if the last day of S/R treatment. If the participant was symptomatic and hospitalized, samples were taken on the Post-treatment+2, +5, +9, +16 assessment days, and at the Post-Treatment +28 Day. Assessment of samples was done by quantitative RT-PCR.

  19. Number of Participants With Resistance-associated Mutations Detected in the Neuraminidase (NA) and Hemagglutinin (HA) Gene of Influenza A and B Viruses in Nasopharyngeal Swabs and Endotracheal/BAL Samples [ Time Frame: Baseline (Day 1) and up to 42 days ]
    Nasopharyngeal swabs and endotracheal /BAL samples were collected for viral susceptibility analysis. Susceptibility analyses consisted of phenotyping and genotyping. Resistance mutations were detected by genotyping. Viral susceptibility to zanamivir and oral oseltamivir at Baseline and throughout treatment determined by NA and HA (gene of influenza A and B viruses) sequence analysis and NA enzyme inhibition. Number of participants with viral mutation events are summarized, this includes all resistance mutations (substitutions) i.e. those present at Baseline and those that emerged during treatment.

  20. Number of Participants With Any Adverse Event (AE) Considered to be Related to Study Treatment [ Time Frame: Up to 42 days ]
    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 AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse. All AEs were assessed by the Investigator as related or not related to the study treatment.

  21. Number of Participants With Any Severe or Grade 3/4 AE [ Time Frame: Up to 42 days ]
    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 AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse. AEs that occurred during the study were evaluated by the Investigator and graded according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) table for grading the severity of AEs. Grade 3=severe; Grade 4=potentially life threatening.

  22. Number of Participants Who Permanently Discontinued the Study Treatment Due to an AE [ Time Frame: Up to 42 days ]
    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 AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse.

  23. Number of Participants Who Were Permanently Discontinued From the Study Due to an AE [ Time Frame: Up to 42 days ]
    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 AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse.

  24. Number of Participants With Any Severe or Grade 3/4 Treatment-related AE [ Time Frame: Up to 42 days ]
    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 AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse. AEs that occurred during the study were evaluated by the Investigator and graded according to the DAIDS table for grading the severity of adult and pediatric AEs. Grade 3=severe; Grade 4=potentially life threatening. All AEs were assessed by the Investigator as related or not related to the study treatment.

  25. Number of Participants With the Indicated Chemistry Laboratory Values Shifts From Baseline (Day 1) and up to 42 Days [ Time Frame: Baseline (Day 1) and up to 42 days ]
    Samples for laboratory assessments were collected at Baseline (Day 1), Day 3, Day 5/6, Day 8, Day 10/11 (or last day of randomized treatment), switch/rescue (S/R) Day 1, S/R Day 3, and S/R Day 5/6 (last day of S/R treatment for those participants who utilized this option), Post-Treatment +2 (if hospitalized), and Post-Treatment +5, +16, and +28 Days. Clinical chemistry parameters included albumin, alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino tranferase (AST), total bilirubin, calcium, creatine kinase, chloride, carbon dioxide content (CO2), creatinine, potassium, magnesium, sodium. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade (G) 1=mild, G2= moderate, G3=severe and G4=potentially life threatening. The number of participants with values that were G1, G2, G3 and G4 relative to the normal range are summarized.

  26. Number of Participants With the Indicated Hematology Values Shifts From Baseline (Day 1) and up to 42 Days [ Time Frame: Baseline (Day 1) and up to 42 days ]
    Blood samples for laboratory assessments were collected at Baseline (Day 1), Day 3, Day 5/6, Day 8, Day 10/11 (or last day of randomized treatment), S/R Day 1, S/R Day 3, and S/R Day 5/6 (last day of S/R treatment for those participants who utilized this option), Post-Treatment +2 (if hospitalized), and Post-Treatment +5, +16, and +28 Days. Hematology parameters included hemoglobin, lymphocytes, total neutrophils, platelet count, and white blood cell (WBC) count. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade (G) 1=mild, G2= moderate, G3=severe and G4=potentially life threatening. The number of participants with values that were G1, G2, G3 and G4 relative to the normal range for the indicated hematology parameters is summarized. Baseline is defined as the pre-dose value collected on Study Day 1.

  27. Number of Participants With the Indicated Treatment-emergent (TE) Grade (G) 3/4 Clinical Chemistry Toxicities [ Time Frame: Baseline (Day 1) and up to 42 days ]
    A toxicity was considered to be TE if it was greater than the Baseline grade, and if it had developed or increased post-Baseline in intensity (and prior to the last dose of investigational product). Clinical chemistry parameters included albumin, ALP, ALT, AST, total bilirubin, calcium, creatine kinase, chloride, CO2/bicarbonate, creatinine, potassium, magnesium and sodium. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade 3=severe and Grade 4=potentially life threatening. Baseline is defined as the pre-dose value collected on Study Day 1.

  28. Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Hematology Toxicities [ Time Frame: Baseline (Day 1) and up to 42 days ]
    A toxicity was considered to be TE if it was greater than the Baseline grade, and if it had developed or increased post-Baseline in intensity (and prior to the last dose of investigational product). The hematology parameters included hemoglobin, lymphocytes, total neutrophils, platelet count, and WBC count. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade 3=severe and Grade 4=potentially life threatening. Baseline is defined as the pre-dose value collected on Study Day 1.

  29. Median Quantity of Oxygen Delivery Measured at Baseline (Day 1) and During the Study [ Time Frame: Baseline (Day 1) and during the study ]
    Oxygen delivery were assessed three times daily at Baseline (Day 1) and during the treatment period/hospitalization (ideally at least 6 hours apart) and once daily during inpatient/hospitalization and once at Post +5 days, +16 days, and +28 days clinic visits. The median quantity of oxygen delivery during the study was not summarized since the data was not collected in a way to accurately calculate values. Baseline is defined as the pre-dose value collected on Study Day 1.

  30. Number of Participants Assessed as Normal/Abnormal (Clinically Significant [CS] and Not Clinically Significant [NCS]) for 12-lead Electrocardiogram (ECG) at Baseline (Day 1) and Day 4 [ Time Frame: Baseline (Day 1) and Day 4 ]
    On Baseline/Day 1, a 12-lead ECG was obtained within approximately 24 hours prior to dosing. The number of participants with an ECG status of normal and abnormal CS or NCS, as determined by the Investigator, is reported. Normal=all ECG parameters within the accepted normal ranges. Abnormal=ECG findings outside of normal ranges. CS=ECG with a CS abnormality that meets exclusion criteria. NCS=ECG with an abnormality that is not CS nor meets exclusion criteria, per Investigator, based on reasonable standards of clinical judgment. In the original protocol ECGs were also done on Day 4, however, amendment 2 removed this requirement and therefore not all participants had Day 4 ECGs.

  31. Serum Concentration of IV Zanamivir [ Time Frame: Day 1 and Day 4 ]
    Pharmacokinetic samples were collected at four time points to characterize peak concentration (end of infusion; C[EOI]) after the first dose on Day 1 and on Day 4 to characterize the pre-dose concentration (C[0]), the peak concentration C(EOI), and the trough concentration at 11-12 hours post-dose (C[12]) of zanamavir. Data was summarized by Creatinine clearance (CL) Category. The dose on Day 1 is the initial dose (unadjusted) and the dose on Day 4 is the maintenance dose.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female aged 16 years; 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.
  • Vital signs criteria defined as 3 or more of the following at Baseline:

    1. Presence of fever [oral temperature of 38°C or equivalent] at Baseline. However, this requirement is waived if the subject has a history of fever within in the 24 hours prior to Baseline; or, if the subject reported symptoms of feverishness at some time during the 48 hours prior to Baseline.

      AND at least 2 out of the following 4:

    2. Oxygen saturation <95% on room air by trans-cutaneous method or need for any supplemental oxygenation or ventilatory support, 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 oxygen saturation of at least 3% below the patient's historical baseline oxygen saturation will satisfy this criterion.
    3. Respiration rate >24 breaths per minute. For those subjects who require ventilatory support or oxygen supplementation, this requirement is waived.
    4. Heart rate >100 beats per minute.
    5. Systolic blood pressure <90 mmHg.
  • 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.
  • Clinical symptoms of influenza with positive influenza diagnostic test result or strong suspicion of influenza illness based on clinical symptoms and local surveillance information.
  • Subjects willing and able to give written informed consent to participate in the study and to adhere to the procedures stated in the protocol, or legally acceptable representative willing and able to give written informed consent on behalf of the subject for minors, unconscious adults and those incapable of consenting themselves due to their medical condition, or included as permitted by local regulatory authorities, IRB/IECs or local laws.
  • Severity of any medical illness that, in the Investigator's judgement, justifies hospitalization of the subject for treatment and supportive care
  • 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

Exclusion Criteria:

  • Subjects who have taken more than a total of 3 days (6 doses) of approved anti-influenza therapy in the period from onset of symptoms and prior to enrolment.
  • 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 with creatinine clearance ≤10 mL/min who are not being treated with continuous renal replacement therapy (CRRT).
  • Subjects who require Extra Corporeal Membrane Oxygenation (ECMO) at Baseline
  • Subjects who require routine/intermittent hemodialysis or continuous peritoneal dialysis (due to inability to provide appropriate dosing schedule for oseltamivir) at Baseline. CRRT modalities are allowed.
  • Liver toxicity criteria based on local laboratory results obtained within 24 hours of Baseline:

    1. ALT or AST 3xULN and bilirubin 2xULN
    2. ALT 5xULN
  • Underlying chronic liver disease with evidence of severe liver impairment.
  • History of severe 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.
  • Females who are pregnant or are breastfeeding.
  • Treatment with investigational parenteral anti-influenza drugs (IV peramivir, IV zanamivir or IV oseltamivir) in the 4 weeks prior to Baseline.
  • French and Korean subjects: the French or Korean subject has participated in any study using an investigational drug during the previous 30 days.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01231620


Locations
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United States, Alabama
GSK Investigational Site
Birmingham, Alabama, United States, 35249
United States, Arizona
GSK Investigational Site
Phoenix, Arizona, United States, 85023
United States, California
GSK Investigational Site
Chula Vista, California, United States, 91911
GSK Investigational Site
Escondido, California, United States, 92025
GSK Investigational Site
Fullerton, California, United States, 92835
GSK Investigational Site
La Jolla, California, United States, 92037
GSK Investigational Site
La Mesa, California, United States, 91942
GSK Investigational Site
Oceanside, California, United States, 92056
United States, Colorado
GSK Investigational Site
Aurora, Colorado, United States, 80045
United States, Connecticut
GSK Investigational Site
Stamford, Connecticut, United States, 06902
United States, Florida
GSK Investigational Site
Orlando, Florida, United States, 32806
GSK Investigational Site
Sarasota, Florida, United States, 34239
GSK Investigational Site
Sunrise, Florida, United States, 33323
United States, Georgia
GSK Investigational Site
Atlanta, Georgia, United States, 30342
GSK Investigational Site
Augusta, Georgia, United States, 30912
United States, Idaho
GSK Investigational Site
Idaho Falls, Idaho, United States, 83404
United States, Illinois
GSK Investigational Site
Chicago, Illinois, United States, 60611
GSK Investigational Site
Oak Park, Illinois, United States, 60302
GSK Investigational Site
Peoria, Illinois, United States, 61637
United States, Iowa
GSK Investigational Site
Council Bluffs, Iowa, United States, 51503
United States, Kansas
GSK Investigational Site
Topeka, Kansas, United States, 66604
United States, Kentucky
GSK Investigational Site
Louisville, Kentucky, United States, 40241
United States, Massachusetts
GSK Investigational Site
Boston, Massachusetts, United States, 02115
United States, Michigan
GSK Investigational Site
Royal Oak, Michigan, United States, 48073
GSK Investigational Site
Troy, Michigan, United States, 48085
United States, Missouri
GSK Investigational Site
Saint Louis, Missouri, United States, 63110-1093
United States, Montana
GSK Investigational Site
Missoula, Montana, United States, 59802
United States, Nevada
GSK Investigational Site
Las Vegas, Nevada, United States, 89109
United States, New York
GSK Investigational Site
Valhalla, New York, United States, 10595
United States, North Carolina
GSK Investigational Site
Asheville, North Carolina, United States, 28801
GSK Investigational Site
Chapel Hill, North Carolina, United States, 27599-7215
United States, North Dakota
GSK Investigational Site
Bismarck, North Dakota, United States, 58504
United States, Ohio
GSK Investigational Site
Cleveland, Ohio, United States, 44195
GSK Investigational Site
Columbus, Ohio, United States, 43215
GSK Investigational Site
Toledo, Ohio, United States, 43608
United States, Pennsylvania
GSK Investigational Site
Bethlehem, Pennsylvania, United States, 18105
GSK Investigational Site
Philadelphia, Pennsylvania, United States, 19107
United States, Texas
GSK Investigational Site
Houston, Texas, United States, 77030
United States, Virginia
GSK Investigational Site
Roanoke, Virginia, United States, 24013
United States, Wisconsin
GSK Investigational Site
Marshfield, Wisconsin, United States, 54449
Australia, New South Wales
GSK Investigational Site
Westmead, New South Wales, Australia, 2145
Australia, Queensland
GSK Investigational Site
Herston, Queensland, Australia, 4029
Australia, South Australia
GSK Investigational Site
Adelaide, South Australia, Australia, 5000
GSK Investigational Site
Bedford Park, South Australia, Australia, 5043
Australia, Victoria
GSK Investigational Site
Clayton, Victoria, Australia, 3168
GSK Investigational Site
Heidelberg, Victoria, Australia, 3084
GSK Investigational Site
Melbourne, Victoria, Australia, 3004
GSK Investigational Site
Melbourne, Victoria, Australia, 3050
Australia, Western Australia
GSK Investigational Site
Perth, Western Australia, Australia, 6000
Belgium
GSK Investigational Site
Brussel, Belgium, 1090
GSK Investigational Site
Bruxelles, Belgium, 1070
GSK Investigational Site
Leuven, Belgium, 3000
GSK Investigational Site
Liege, Belgium, 4000
Brazil
GSK Investigational Site
Rio de Janeiro, Brazil, 21040-900
GSK Investigational Site
São Paulo, Brazil, 01308-050
Canada, Alberta
GSK Investigational Site
Calgary, Alberta, Canada, T1Y 6J4
GSK Investigational Site
Calgary, Alberta, Canada, T2N 2T9
Canada, Nova Scotia
GSK Investigational Site
Halifax, Nova Scotia, Canada, B3H 3A7
Canada, Ontario
GSK Investigational Site
Hamilton, Ontario, Canada, L8N 4A6
GSK Investigational Site
Toronto, Ontario, Canada, M5G 2C4
Canada, Quebec
GSK Investigational Site
Chicoutimi, Quebec, Canada, G7H 5H6
GSK Investigational Site
Montreal, Quebec, Canada, H1T 2M4
GSK Investigational Site
Montreal, Quebec, Canada, H2W1T8
GSK Investigational Site
Trois-Rivières, Quebec, Canada, G8Z 3R9
China, Hainan
GSK Investigational Site
Haikou, Hainan, China, 570311
China, Hunan
GSK Investigational Site
Changsha, Hunan, China, 410005
China, Jiangxi
GSK Investigational Site
Nanchang, Jiangxi, China, 330006
China, Jilin
GSK Investigational Site
Changchun, Jilin, China, 130041
China, Shaanxi
GSK Investigational Site
Xian, Shaanxi, China, 710032
China, Zhejiang
GSK Investigational Site
Hangzhou, Zhejiang, China, 310003
China
GSK Investigational Site
Beijing, China, 100015
GSK Investigational Site
Beijing, China, 100044
GSK Investigational Site
Chengdu, China, 610041
GSK Investigational Site
Chongqing, China, 400016
GSK Investigational Site
Guangzhou, China, 510120
GSK Investigational Site
Hangzhou, China, 310016
GSK Investigational Site
Shanghai, China, 200025
GSK Investigational Site
Tianjin, China, 300052
Colombia
GSK Investigational Site
Bogotá, Colombia
Czechia
GSK Investigational Site
Brno - Bohunice, Czechia, 625 00
GSK Investigational Site
Brno, Czechia, 625 00
GSK Investigational Site
Hradec Kralove, Czechia, 500 05
GSK Investigational Site
Praha 8, Czechia, 180 01
Denmark
GSK Investigational Site
Aarhus N, Denmark, 8200
GSK Investigational Site
Hvidovre, Denmark, DK-2650
GSK Investigational Site
Odense C, Denmark, 5000
France
GSK Investigational Site
Dijon Cedex, France, 21079
GSK Investigational Site
Limoges cedex, France, 87042
GSK Investigational Site
Nîmes cedex 9, France, 30029
GSK Investigational Site
Orléans cedex 2, France, 45067
GSK Investigational Site
Poitiers Cedex, France, 86021
GSK Investigational Site
Tours cedex 9, France, 37044
Germany
GSK Investigational Site
Ulm, Baden-Wuerttemberg, Germany, 89081
GSK Investigational Site
Erlangen, Bayern, Germany, 91054
GSK Investigational Site
Regensburg, Bayern, Germany, 93053
GSK Investigational Site
Hannover, Niedersachsen, Germany, 30625
GSK Investigational Site
Homburg, Saarland, Germany, 66421
Greece
GSK Investigational Site
Chaidari, Greece, 12462
GSK Investigational Site
Goudi, Athens, Greece, 11527
Hong Kong
GSK Investigational Site
Kwun Tong, Hong Kong
GSK Investigational Site
Shatin, Hong Kong
GSK Investigational Site
Tuen Mun, Hong Kong
Hungary
GSK Investigational Site
Debrecen, Hungary, 4031
GSK Investigational Site
Kaposvár, Hungary, 7400
GSK Investigational Site
Miskolc, Hungary, 3529
GSK Investigational Site
Szombathely, Hungary, 9700
GSK Investigational Site
Székesfehérvár, Hungary, 8000
India
GSK Investigational Site
Bangalore, India, 560010
GSK Investigational Site
Civil Lines, India, 141001
GSK Investigational Site
Lucknow, India, 226003
GSK Investigational Site
Lucknow, India, 226005
GSK Investigational Site
Pune, India, 411004
GSK Investigational Site
Pune, India, 411018
GSK Investigational Site
Trivandrum, India, 695029
Korea, Republic of
GSK Investigational Site
Guro Gu, Korea, Republic of, 152703
GSK Investigational Site
Gyeonggi, Korea, Republic of, 442-723
GSK Investigational Site
Kangwon-do, Korea, Republic of, 220-701
GSK Investigational Site
Seoul, Korea, Republic of, 150-030
GSK Investigational Site
Seoul, Korea, Republic of, 150-950
Mexico
GSK Investigational Site
Cuautitlán, Estado De México, Estado De México, Mexico, 54800
GSK Investigational Site
Guadalajara, Jalisco, Mexico, 44280
GSK Investigational Site
San Nicolas de los Garza, Nuevo León, Mexico, 66480
GSK Investigational Site
Aguascalientes, Mexico, 20230
GSK Investigational Site
Chihuahua, Mexico, 31238
Netherlands
GSK Investigational Site
Nijmegen, Netherlands, 6500 HB
New Zealand
GSK Investigational Site
Auckland, New Zealand, 1001
GSK Investigational Site
Auckland, New Zealand, 1701
GSK Investigational Site
Auckland, New Zealand
GSK Investigational Site
Christchurch, New Zealand, 8001
GSK Investigational Site
Hamilton, New Zealand, 3204
GSK Investigational Site
Hastings, New Zealand, 4120
GSK Investigational Site
Newtown, New Zealand
Norway
GSK Investigational Site
Bergen, Norway, 5053
GSK Investigational Site
Trondheim, Norway, 7030
Poland
GSK Investigational Site
Chorzow, Poland, 41-500
GSK Investigational Site
Debica, Poland, 39-200
GSK Investigational Site
Trzebnica, Poland, 55-100
GSK Investigational Site
Warszawa, Poland, 01-201
Russian Federation
GSK Investigational Site
Barnaul, Russian Federation, 656024
GSK Investigational Site
Barnaul, Russian Federation, 656038
GSK Investigational Site
Saint-Petersburg, Russian Federation, 191167
GSK Investigational Site
Sankt-Peterburg, Russian Federation, 197022
GSK Investigational Site
Smolensk, Russian Federation, 214006
Slovakia
GSK Investigational Site
Bratislava, Slovakia, 833 05
GSK Investigational Site
Martin, Slovakia, 036 59
South Africa
GSK Investigational Site
Middelburg, Mpumalanga, South Africa, 1055
GSK Investigational Site
Bellville, South Africa, 7530
GSK Investigational Site
Die Wilgers, South Africa, 0041
GSK Investigational Site
Les Marais, South Africa, 0084
GSK Investigational Site
Panorama, South Africa, 7500
GSK Investigational Site
Worcester, South Africa, 6850
Spain
GSK Investigational Site
Alicante, Spain, 03010
GSK Investigational Site
Badalona, Spain, 08916
GSK Investigational Site
Barcelona, Spain, 08003
GSK Investigational Site
Granada, Spain, 18012
GSK Investigational Site
Granada, Spain, 18014
GSK Investigational Site
L'Hospitalet de Llobregat, Spain, 08907
GSK Investigational Site
Madrid, Spain, 28007
GSK Investigational Site
Madrid, Spain, 28040
GSK Investigational Site
Madrid, Spain, 28046
GSK Investigational Site
Murcia, Spain, 30003
GSK Investigational Site
Oviedo, Spain, 33006
GSK Investigational Site
Pama de Mallorca, Spain, 07010
Taiwan
GSK Investigational Site
Taipei, Taiwan, 112
Thailand
GSK Investigational Site
Bangkok, Thailand, 10400
GSK Investigational Site
Bangkok, Thailand, 10700
United Kingdom
GSK Investigational Site
Bristol, United Kingdom, BS2 8HW
GSK Investigational Site
Cardiff, United Kingdom, CF14 4XW
GSK Investigational Site
Liverpool, United Kingdom, L7 8XP
GSK Investigational Site
Manchester, United Kingdom, M13 9WL
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Layout table for investigator information
Study Director: GSK Clinical Trials GlaxoSmithKline

Additional Information:
Study Data/Documents: Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: 114373
For additional information about this study please refer to the GSK Clinical Study Register
Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: 114373
For additional information about this study please refer to the GSK Clinical Study Register
Clinical Study Report  This link exits the ClinicalTrials.gov site
Identifier: 114373
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: 114373
For additional information about this study please refer to the GSK Clinical Study Register
Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: 114373
For additional information about this study please refer to the GSK Clinical Study Register
Informed Consent Form  This link exits the ClinicalTrials.gov site
Identifier: 114373
For additional information about this study please refer to the GSK Clinical Study Register
Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: 114373
For additional information about this study please refer to the GSK Clinical Study Register

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01231620    
Other Study ID Numbers: 114373
First Posted: November 1, 2010    Key Record Dates
Results First Posted: November 20, 2017
Last Update Posted: October 15, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
Keywords provided by GlaxoSmithKline:
Seasonal Influenza
Pandemic
Orthomyxoviridae Infections
Influenza
Influenza A Virus, H1N1 Subtype
Enzyme Inhibitors
Influenza, seasonal
Respiratory Tract Diseases
Zanamivir
Pharmacologic Actions
Antiviral Agents
Anti-Infective Agents
H1N1
Neuraminidase inhibitor
Influenza B virus
Additional relevant MeSH terms:
Layout table for MeSH terms
Influenza, Human
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Oseltamivir
Zanamivir
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action