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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 626
- 试验地点
- 1
- 主要终点
- Time to Clinical Response (TTCR) in Participants With Confirmed Influenza
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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 16 years; 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.
- •Vital signs criteria defined as 3 or more of the following at Baseline:
- •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:
- •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.
- •Respiration rate >24 breaths per minute. For those subjects who require ventilatory support or oxygen supplementation, this requirement is waived.
- •Heart rate >100 beats per minute.
- •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
排除标准
- •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:
- •ALT or AST 3xULN and bilirubin 2xULN
- •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.
研究组 & 干预措施
Intravenous (IV) Zanamivir 300mg Twice Daily
300mg of IV zanamivir infusion twice daily plus oral oseltamivir placebo twice daily
干预措施: Zanamivir (Drug)
Intravenous (IV) Zanamivir 300mg Twice Daily
300mg of IV zanamivir infusion twice daily plus oral oseltamivir placebo twice daily
干预措施: Placebo to match oseltamivir (Drug)
Intravenous (IV) Zanamivir 600mg Twice Daily
600mg of IV zanamivir infusion twice daily plus oral oseltamivir placebo twice daily
干预措施: Zanamivir (Drug)
Intravenous (IV) Zanamivir 600mg Twice Daily
600mg of IV zanamivir infusion twice daily plus oral oseltamivir placebo twice daily
干预措施: Placebo to match oseltamivir (Drug)
Oral Oseltamivir 75mg Twice Daily
75mg oral oseltamivir twice daily plus intravenous placebo zanamivir twice daily
干预措施: Placebo to match zanamivir (Drug)
Oral Oseltamivir 75mg Twice Daily
75mg oral oseltamivir twice daily plus intravenous placebo zanamivir twice daily
干预措施: Oseltamivir (Drug)
结局指标
主要结局
Time to Clinical Response (TTCR) in Participants With Confirmed Influenza
时间窗: 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.
次要结局
- Percentage of Participants With Respiratory Improvement(Up to 42 days)
- Number of Participants With All Cause and Attributable Mortality at Day 14, at Day 28, and at the End of Study Visit(On or before Day 14, Day 28, End of Study Visit (assessed up to 42 days))
- Change From Baseline in the Katz Activities of Daily Living (ADL) Score and Each ADL Activity Score(Baseline (Day 1) and up to 42 days)
- Median Time to Return to Pre-morbid Functional Status as Measured by the Katz ADL Score and Each ADL Activity Score(Up to 42 days)
- 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(Up to 42 days)
- Median Time to Return to the Pre-morbid Level of Activity as Measured by the 3-point Scale(Up to 42 days)
- Number of Participants With the Indicated Clinical Symptoms of Influenza(Up to 42 days)
- Median Time of Duration of Clinical Symptoms of Influenza(Up to 42 days)
- Number of Participants With Complications of Influenza and Associated Antibiotic Use(Up to 42 days)
- Number of Participants With the Indicated Ventilation Status: Modality of Invasive and Non-invasive Ventilator Support and Oxygen Supplementation(Up to 42 days)
- Median Time of Duration of Invasive and Non-invasive Ventilator Support and Oxygen Supplementation(Baseline (Day 1) and up to 42 days)
- Median Time of Duration of Hospitalization and Intensive Care Unit (ICU) Stay(Day 1 to the end of the study (assessed up to 42 days))
- Median Time to the Absence of Fever and Improved Respiratory Status, Oxygen Saturation, Heart Rate, and Systolic Blood Pressure(Baseline (Day 1) and up to 42 days)
- Median Time to Virologic Improvement(Baseline (Day 1) and up to 42 days)
- Change From Baseline in Quantitative Virus Culture From Nasopharyngeal Swabs Positive at Baseline(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)
- Change From Baseline Viral Load (Influenza A or B) by qPCR From Nasopharyngeal Swabs Positive at Baseline(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)
- Number of Participants With no Detectable Viral RNA and the Absence of Cultivable Virus in Lower Respiratory Samples (Bronchoalveolar Lavage Sample [BAL], Endotracheal Aspirate)(Baseline (Day 1) and up to 42 days)
- Median Time to no Detectable Viral RNA and the Absence of Cultivable Virus in Any Obtained Sample (Upper and Lower Respiratory Samples)(Baseline (Day 1) and up to 42 days)
- 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(Baseline (Day 1) and up to 42 days)
- Number of Participants With Any Adverse Event (AE) Considered to be Related to Study Treatment(Up to 42 days)
- Number of Participants With Any Severe or Grade 3/4 AE(Up to 42 days)
- Number of Participants Who Permanently Discontinued the Study Treatment Due to an AE(Up to 42 days)
- Number of Participants Who Were Permanently Discontinued From the Study Due to an AE(Up to 42 days)
- Serum Concentration of IV Zanamivir(Day 1 and Day 4)
- Number of Participants With Any Severe or Grade 3/4 Treatment-related AE(Up to 42 days)
- Number of Participants With the Indicated Chemistry Laboratory Values Shifts From Baseline (Day 1) and up to 42 Days(Baseline (Day 1) and up to 42 days)
- Number of Participants With the Indicated Hematology Values Shifts From Baseline (Day 1) and up to 42 Days(Baseline (Day 1) and up to 42 days)
- Number of Participants With the Indicated Treatment-emergent (TE) Grade (G) 3/4 Clinical Chemistry Toxicities(Baseline (Day 1) and up to 42 days)
- Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Hematology Toxicities(Baseline (Day 1) and up to 42 days)
- Median Quantity of Oxygen Delivery Measured at Baseline (Day 1) and During the Study(Baseline (Day 1) and during the study)
- 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(Baseline (Day 1) and Day 4)