Clinical trial NCT01527110: 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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Influenza, Human
Keywords: zanamivir
Seasonal Influenza
H1N1
intravenous
neuraminidase inhibitor
Pandemic
Relenza
Influenza B virus
Influenza A virus
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-02-06
Enrollment: 21
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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
timeFrame: Start of treatment (Day 1) up to follow-up (Day 33)
measure: 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
timeFrame: Baseline (Day 1) to Day 5
measure: Number of Participants With Clinical Chemistry Parameters of Creatinine, Direct Bilirubin and Total Bilirubin Outside the Normal Reference Range at Any Time During Treatment
timeFrame: Baseline (Day 1) to Day 5
measure: 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
timeFrame: Baseline (Day 1) to Day 5
measure: Number of Participants With Clinical Chemistry Parameters of Albumin and Total Protein Outside the Normal Reference Range at Any Time During Treatment
timeFrame: Baseline (Day 1) to Day 5
measure: 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
timeFrame: Baseline (Day 1) to Day 5
measure: Mean Change From Baseline in Albumin and Total Protein at the Indicated Time Points
timeFrame: Baseline (Day 1), Day 3 and Day 5
measure: Mean Change From Baseline in ALT, ALP, Creatine Kinase and AST at the Indicated Time Points
timeFrame: Baseline (Day 1), Day 3 and Day 5
measure: Mean Change From Baseline in Creatinine, Direct Bilirubin and Total Bilirubin at the Indicated Time Points
timeFrame: Baseline (Day 1), Day 3 and Day 5
measure: Mean Change From Baseline in Sodium, Calcium, Potassium, Chloride, Magnesium, Carbon Dioxide Content/Bicarbonate and Urea/BUN at the Indicated Time Points
timeFrame: Baseline (Day 1), Day 3 and Day 5
measure: Mean Change From Baseline in Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes and Total Neutrophils at the Indicated Time Points
timeFrame: Baseline, Day 3 and Day 5
measure: Mean Change From Baseline in Counts of WBC and Platelets at the Indicated Time Points
timeFrame: Baseline (Day 1), Day 3 and Day 5
measure: Mean Change From Baseline in Hemoglobin at the Indicated Time Points
timeFrame: Baseline (Day 1), Day 3 and Day 5
measure: Mean Change Baseline in Hematocrit at the Indicated Time Points
timeFrame: Baseline (Day 1), Day 3 and Day 5
measure: Number of Participants With Toxicity Shifts From Baseline in Clinical Chemistry Over Period
timeFrame: Baseline (Day 1), Day 3 and Day 5
measure: Number of Participants With Toxicity Shifts From Baseline in Hematology Parameters Over Period
timeFrame: Baseline (Day 1), Day 3 and Day 5
measure: Number of Participants of Treatment Emergent Toxicities in Clinical Chemistry and Hematology Over Period
timeFrame: Day 1, Day 3 and Day 5
measure: Mean Heart Rate (HR) of Participants Over Period
timeFrame: Baeline (Day 1) to Day 6
measure: Mean Systolic and Diastolic Blood Pressure (SBP and DBP) of Participants Over Period
timeFrame: Baseline (Day 1) to Day 6
measure: Mean Oxygen Saturation (OS) of Participants Over Period
timeFrame: Baseline (Day 1) to Day 6
measure: Mean Respiratory Rate (RR) of Participants Over Period
timeFrame: Baseline (Day 1) to Day 6
measure: Mean Temperature of Participants Over Period
timeFrame: Baseline (Day 1) to Day 6
measure: Number of Participants With Abnormal Clinically Significant Electrocardiograph (ECG) Findings Over Period
timeFrame: Baseline (Day 1, pre-dose) and Day 4
measure: Percentage of Participants With Abnormal Clinically Significant ECG Findings Over Period
timeFrame: Baseline ( pre-dose Day 1) and Day 4
Secondary outcomes:
measure: Median Time to Absence of Fever, Improved Respiratory Status, Improved OS, Improved HR and Improved SBP Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Median Time to Clinical Response Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Median Time to Return to Pre-morbid Level of Activity Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Number of Participants With and Without Use of Modality of Invasive, Non-invasive Ventilatory Support and Oxygen Supplementation Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Median Duration of Use of Invasive and Non-invasive Ventilatory Support and Oxygen Supplementation Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Median Duration of Intensive Care Unit (ICU) Stay for the Participants Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Median Duration of Hospital Stay for the Participants Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Mean 50% Inhibitory Concentration (IC50) for Phenotypes of Influenza for the Measure of Viral Susceptibility to Zanamivir at All Visits
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Number of Participants With or Without Treatment Emergent Resistance or Suspected Treatment Emergent Resistance to Zanamivir Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Number of Participants of Clinical Symptoms of Influenza Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Median Duration of Clinical Symptoms of Influenza Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Number of Participants With Complications of Influenza and Associated Use of Antibiotics Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Median Time to Virologic Improvement Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Percentage of Participants With Undetectable Viral RNA and Absence Cultivable Virus From Samples Obtained From Nasopharyngeal Samples Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Percentage of Participants With Undetectable Viral RNA and Absence of Cultivable Virus in Lower Respiratory Samples Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Median Time to no Detectable Viral RNA by Quantitative RT-PCR and Viral Culture From Nasopharyngeal Samples Over Period
timeFrame: Baseline (Day 1) to Day 33 (follow-up)
measure: Mean Change From Baseline in Quantitative Viral Load Measured by RT-PCR From Nasopharyngeal Swabs Positive at Baseline Over Period
timeFrame: Baseline (Day 1) up to Day 33 (follow-up)
measure: Mean Change From Baseline in Quantitative Viral Load Measured by Viral Culture From Nasopharyngeal Swabs Over Period
timeFrame: Baseline (Day 1) up to Day 33 (follow-up)
Other outcomes:
Locations:
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Miyagi
country: Japan
facility: GSK Investigational Site
city: Miyagi
country: Japan
facility: GSK Investigational Site
city: Okayama
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Shizuoka
country: Japan
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Watanabe A, Yates PJ, Murayama M, Soutome T, Furukawa H. Evaluation of safety and efficacy of intravenous zanamivir in the treatment of hospitalized Japanese patients with influenza: an open-label, single-arm study. Antivir Ther. 2015;20(4):415-23. doi: 10.3851/IMP2922. Epub 2014 Dec 3.