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)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- Number of Participants With Clinical Chemistry Parameters of Creatinine, Direct Bilirubin and Total Bilirubin Outside the Normal Reference Range at Any Time During Treatment
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal); or,
- •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.
- •Moderate to severe tachypnea (respiratory rate >=24/minute) OR
- •Moderate to severe dyspnea (unable to speak in full sentences) OR
- •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
- •Hemodynamic instability, defined as systolic blood pressure <90 mmHg or heart rate >100 beats per minute OR
- •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.
排除标准
- •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:
- •ALT or AST >=3xULN and bilirubin >=2xULN
- •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:
- •QTcB or QTcF >480 msec
- •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.
研究组 & 干预措施
Intravenous (IV) zanamivir 600mg twice daily
600mg of IV zanamivir infusion twice daily
干预措施: Intravenous (IV) zanamivir (Drug)
结局指标
主要结局
Number of Participants With Clinical Chemistry Parameters of Creatinine, Direct Bilirubin and Total Bilirubin Outside the Normal Reference Range at Any Time During Treatment
时间窗: Baseline (Day 1) to Day 5
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.
Mean Change From Baseline in Sodium, Calcium, Potassium, Chloride, Magnesium, Carbon Dioxide Content/Bicarbonate and Urea/BUN at the Indicated Time Points
时间窗: Baseline (Day 1), Day 3 and Day 5
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.
Number of Participants With Clinical Chemistry Parameters of Albumin and Total Protein Outside the Normal Reference Range at Any Time During Treatment
时间窗: Baseline (Day 1) to Day 5
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
时间窗: Baseline (Day 1) to Day 5
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.
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
时间窗: Start of treatment (Day 1) up to follow-up (Day 33)
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
时间窗: Baseline (Day 1) to Day 5
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 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
时间窗: Baseline (Day 1) to Day 5
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.
Mean Change From Baseline in Albumin and Total Protein at the Indicated Time Points
时间窗: Baseline (Day 1), Day 3 and Day 5
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
时间窗: Baseline (Day 1), Day 3 and Day 5
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
时间窗: Baseline (Day 1), Day 3 and Day 5
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 Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes and Total Neutrophils at the Indicated Time Points
时间窗: Baseline, Day 3 and Day 5
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
时间窗: Baseline (Day 1), Day 3 and Day 5
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
时间窗: Baseline (Day 1), Day 3 and Day 5
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
时间窗: Baseline (Day 1), Day 3 and Day 5
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
时间窗: Baseline (Day 1), Day 3 and Day 5
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
时间窗: Baseline (Day 1), Day 3 and Day 5
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
时间窗: Day 1, Day 3 and Day 5
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
时间窗: Baeline (Day 1) to Day 6
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
时间窗: Baseline (Day 1) to Day 6
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
时间窗: Baseline (Day 1) to Day 6
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
时间窗: Baseline (Day 1) to Day 6
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
时间窗: Baseline (Day 1) to Day 6
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
时间窗: Baseline (Day 1, pre-dose) and Day 4
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
时间窗: Baseline ( pre-dose Day 1) and Day 4
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).
次要结局
- Number of Participants of Clinical Symptoms of Influenza Over Period(Baseline (Day 1) to Day 33 (follow-up))
- Percentage of Participants With Undetectable Viral RNA and Absence Cultivable Virus From Samples Obtained From Nasopharyngeal Samples Over Period(Baseline (Day 1) to Day 33 (follow-up))
- Median Time to Absence of Fever, Improved Respiratory Status, Improved OS, Improved HR and Improved SBP Over Period(Baseline (Day 1) to Day 33 (follow-up))
- Median Time to Clinical Response Over Period(Baseline (Day 1) to Day 33 (follow-up))
- Number of Participants With and Without Use of Modality of Invasive, Non-invasive Ventilatory Support and Oxygen Supplementation Over Period(Baseline (Day 1) to Day 33 (follow-up))
- Median Time to Return to Pre-morbid Level of Activity Over Period(Baseline (Day 1) to Day 33 (follow-up))
- Median Duration of Use of Invasive and Non-invasive Ventilatory Support and Oxygen Supplementation Over Period(Baseline (Day 1) to Day 33 (follow-up))
- Median Duration of Hospital Stay for the Participants Over Period(Baseline (Day 1) to Day 33 (follow-up))
- Percentage of Participants With Undetectable Viral RNA and Absence of Cultivable Virus in Lower Respiratory Samples Over Period(Baseline (Day 1) to Day 33 (follow-up))
- Mean Change From Baseline in Quantitative Viral Load Measured by Viral Culture From Nasopharyngeal Swabs Over Period(Baseline (Day 1) up to Day 33 (follow-up))
- Median Duration of Intensive Care Unit (ICU) Stay for the Participants Over Period(Baseline (Day 1) to Day 33 (follow-up))
- Mean 50% Inhibitory Concentration (IC50) for Phenotypes of Influenza for the Measure of Viral Susceptibility to Zanamivir at All Visits(Baseline (Day 1) to Day 33 (follow-up))
- Number of Participants With or Without Treatment Emergent Resistance or Suspected Treatment Emergent Resistance to Zanamivir Over Period(Baseline (Day 1) to Day 33 (follow-up))
- Median Duration of Clinical Symptoms of Influenza Over Period(Baseline (Day 1) to Day 33 (follow-up))
- Median Time to no Detectable Viral RNA by Quantitative RT-PCR and Viral Culture From Nasopharyngeal Samples Over Period(Baseline (Day 1) to Day 33 (follow-up))
- Mean Change From Baseline in Quantitative Viral Load Measured by RT-PCR From Nasopharyngeal Swabs Positive at Baseline Over Period(Baseline (Day 1) up to Day 33 (follow-up))
- Number of Participants With Complications of Influenza and Associated Use of Antibiotics Over Period(Baseline (Day 1) to Day 33 (follow-up))
- Median Time to Virologic Improvement Over Period(Baseline (Day 1) to Day 33 (follow-up))