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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT01231620
• Date of registration: 28/10/2010
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline
• Public title: A Study of Intravenous Zanamivir Versus Oral Oseltamivir in Adults and Adolescents Hospitalized With Influenza ZORO
• Scientific 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
• Date of first enrolment: January 15, 2011
• Target sample size: 626
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT01231620
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 3

Countries of recruitment

Argentina, Australia, Belgium, Brazil, Canada, China, Colombia, Czech Republic, Czechia, Denmark, France, Germany, Greece, Hong Kong, Hungary, India, Korea, Republic of, Mexico, Netherlands, New Zealand, Norway, Pakistan, Poland, Russian Federation, Slovakia, South Africa, Spain, Taiwan, Thailand, United Kingdom, United States

Contacts

• Name: GSK Clinical Trials
• Affiliation: GlaxoSmithKline

Key inclusion & exclusion 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.



Age minimum: 16 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Influenza, Human

Intervention(s)

Drug: Placebo to match zanamivir

Drug: Oseltamivir

Drug: Zanamivir

Drug: Placebo to match oseltamivir

Primary Outcome(s)

Time to Clinical Response (TTCR) in Participants With Confirmed Influenza [Time Frame: Up to 42 days]

Secondary Outcome(s)

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)]

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]

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]

Median Time to Return to the Pre-morbid Level of Activity as Measured by the 3-point Scale [Time Frame: Up to 42 days]

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]

Number of Participants Who Were Permanently Discontinued From the Study Due to an AE [Time Frame: Up to 42 days]

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]

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]

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]

Percentage of Participants With Respiratory Improvement [Time Frame: 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 [Time Frame: On or before Day 14, Day 28, End of Study Visit (assessed up to 42 days)]

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]

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]

Number of Participants With Any Severe or Grade 3/4 Treatment-related AE [Time Frame: Up to 42 days]

Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Hematology Toxicities [Time Frame: 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 [Time Frame: Up to 42 days]

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]

Number of Participants Who Permanently Discontinued the Study Treatment Due to an AE [Time Frame: Up to 42 days]

Number of Participants With Any Severe or Grade 3/4 AE [Time Frame: 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) [Time Frame: Baseline (Day 1) and up to 42 days]

Number of Participants With the Indicated Clinical Symptoms of Influenza [Time Frame: Up to 42 days]

Serum Concentration of IV Zanamivir [Time Frame: Day 1 and Day 4]

Median Quantity of Oxygen Delivery Measured at Baseline (Day 1) and During the Study [Time Frame: Baseline (Day 1) and during the study]

Median Time of Duration of Clinical Symptoms of Influenza [Time Frame: Up to 42 days]

Median Time of Duration of Invasive and Non-invasive Ventilator Support and Oxygen Supplementation [Time Frame: Baseline (Day 1) and up to 42 days]

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]

Median Time to Virologic Improvement [Time Frame: Baseline (Day 1) and up to 42 days]

Number of Participants With Any Adverse Event (AE) Considered to be Related to Study Treatment [Time Frame: Up to 42 days]

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]

Number of Participants With Complications of Influenza and Associated Antibiotic Use [Time Frame: 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 [Time Frame: Baseline (Day 1) and up to 42 days]

Secondary ID(s)

114373

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 20/11/2017
• URL: https://clinicaltrials.gov/ct2/show/results/NCT01231620