Clinical trial NCT01231620: A Study of Intravenous Zanamivir Versus Oral Oseltamivir in Adults and Adolescents Hospitalized With Influenza
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Influenza, Human
Keywords: 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
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2010-11-01
Enrollment: 626
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Time to Clinical Response (TTCR) in Participants With Confirmed Influenza
timeFrame: Up to 42 days
Secondary outcomes:
measure: Percentage of Participants With Respiratory Improvement
timeFrame: Up to 42 days
measure: Number of Participants With All Cause and Attributable Mortality at Day 14, at Day 28, and at the End of Study Visit
timeFrame: On or before Day 14, Day 28, End of Study Visit (assessed up to 42 days)
measure: Change From Baseline in the Katz Activities of Daily Living (ADL) Score and Each ADL Activity Score
timeFrame: Baseline (Day 1) and up to 42 days
measure: Median Time to Return to Pre-morbid Functional Status as Measured by the Katz ADL Score and Each ADL Activity Score
timeFrame: Up to 42 days
measure: 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
timeFrame: Up to 42 days
measure: Median Time to Return to the Pre-morbid Level of Activity as Measured by the 3-point Scale
timeFrame: Up to 42 days
measure: Number of Participants With the Indicated Clinical Symptoms of Influenza
timeFrame: Up to 42 days
measure: Median Time of Duration of Clinical Symptoms of Influenza
timeFrame: Up to 42 days
measure: Number of Participants With Complications of Influenza and Associated Antibiotic Use
timeFrame: Up to 42 days
measure: Number of Participants With the Indicated Ventilation Status: Modality of Invasive and Non-invasive Ventilator Support and Oxygen Supplementation
timeFrame: Up to 42 days
measure: Median Time of Duration of Invasive and Non-invasive Ventilator Support and Oxygen Supplementation
timeFrame: Baseline (Day 1) and up to 42 days
measure: Median Time of Duration of Hospitalization and Intensive Care Unit (ICU) Stay
timeFrame: Day 1 to the end of the study (assessed up to 42 days)
measure: Median Time to the Absence of Fever and Improved Respiratory Status, Oxygen Saturation, Heart Rate, and Systolic Blood Pressure
timeFrame: Baseline (Day 1) and up to 42 days
measure: Median Time to Virologic Improvement
timeFrame: Baseline (Day 1) and up to 42 days
measure: Change From Baseline in Quantitative Virus Culture From Nasopharyngeal Swabs Positive at Baseline
timeFrame: 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
measure: Change From Baseline Viral Load (Influenza A or B) by qPCR From Nasopharyngeal Swabs Positive at Baseline
timeFrame: 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
measure: Number of Participants With no Detectable Viral RNA and the Absence of Cultivable Virus in Lower Respiratory Samples (Bronchoalveolar Lavage Sample [BAL], Endotracheal Aspirate)
timeFrame: Baseline (Day 1) and up to 42 days
measure: Median Time to no Detectable Viral RNA and the Absence of Cultivable Virus in Any Obtained Sample (Upper and Lower Respiratory Samples)
timeFrame: Baseline (Day 1) and up to 42 days
measure: 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
timeFrame: Baseline (Day 1) and up to 42 days
measure: Number of Participants With Any Adverse Event (AE) Considered to be Related to Study Treatment
timeFrame: Up to 42 days
measure: Number of Participants With Any Severe or Grade 3/4 AE
timeFrame: Up to 42 days
measure: Number of Participants Who Permanently Discontinued the Study Treatment Due to an AE
timeFrame: Up to 42 days
measure: Number of Participants Who Were Permanently Discontinued From the Study Due to an AE
timeFrame: Up to 42 days
measure: Number of Participants With Any Severe or Grade 3/4 Treatment-related AE
timeFrame: Up to 42 days
measure: Number of Participants With the Indicated Chemistry Laboratory Values Shifts From Baseline (Day 1) and up to 42 Days
timeFrame: Baseline (Day 1) and up to 42 days
measure: Number of Participants With the Indicated Hematology Values Shifts From Baseline (Day 1) and up to 42 Days
timeFrame: Baseline (Day 1) and up to 42 days
measure: Number of Participants With the Indicated Treatment-emergent (TE) Grade (G) 3/4 Clinical Chemistry Toxicities
timeFrame: Baseline (Day 1) and up to 42 days
measure: Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Hematology Toxicities
timeFrame: Baseline (Day 1) and up to 42 days
measure: Median Quantity of Oxygen Delivery Measured at Baseline (Day 1) and During the Study
timeFrame: Baseline (Day 1) and during the study
measure: 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
timeFrame: Baseline (Day 1) and Day 4
measure: Serum Concentration of IV Zanamivir
timeFrame: Day 1 and Day 4
Other outcomes:
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country: Czechia
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country: Denmark
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city: Hvidovre
country: Denmark
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country: Denmark
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city: Dijon Cedex
country: France
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city: Limoges cedex
country: France
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city: Nîmes cedex 9
country: France
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city: Orléans cedex 2
country: France
facility: GSK Investigational Site
city: Poitiers Cedex
country: France
facility: GSK Investigational Site
city: Tours cedex 9
country: France
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city: Ulm
country: Germany
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state: Baden-Wuerttemberg
city: Erlangen
country: Germany
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state: Bayern
city: Regensburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Homburg
country: Germany
facility: GSK Investigational Site
state: Saarland
city: Chaidari
country: Greece
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city: Goudi, Athens
country: Greece
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country: Hong Kong
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city: Shatin
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city: Szombathely
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city: Székesfehérvár
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city: Bangalore
country: India
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city: Civil Lines
country: India
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city: Lucknow
country: India
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city: Lucknow
country: India
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city: Pune
country: India
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city: Pune
country: India
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city: Trivandrum
country: India
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country: Korea, Republic of
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facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
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country: Mexico
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city: San Nicolas de los Garza
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state: Nuevo León
city: Aguascalientes
country: Mexico
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city: Chihuahua
country: Mexico
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city: Nijmegen
country: Netherlands
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country: New Zealand
facility: GSK Investigational Site
city: Auckland
country: New Zealand
facility: GSK Investigational Site
city: Auckland
country: New Zealand
facility: GSK Investigational Site
city: Christchurch
country: New Zealand
facility: GSK Investigational Site
city: Hamilton
country: New Zealand
facility: GSK Investigational Site
city: Hastings
country: New Zealand
facility: GSK Investigational Site
city: Newtown
country: New Zealand
facility: GSK Investigational Site
city: Bergen
country: Norway
facility: GSK Investigational Site
city: Trondheim
country: Norway
facility: GSK Investigational Site
city: Chorzow
country: Poland
facility: GSK Investigational Site
city: Debica
country: Poland
facility: GSK Investigational Site
city: Trzebnica
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Barnaul
country: Russian Federation
facility: GSK Investigational Site
city: Barnaul
country: Russian Federation
facility: GSK Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Sankt-Peterburg
country: Russian Federation
facility: GSK Investigational Site
city: Smolensk
country: Russian Federation
facility: GSK Investigational Site
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country: Slovakia
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country: Slovakia
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state: Mpumalanga
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city: Alicante
country: Spain
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country: Spain
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city: Barcelona
country: Spain
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country: Spain
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city: Granada
country: Spain
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city: L'Hospitalet de Llobregat
country: Spain
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city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Murcia
country: Spain
facility: GSK Investigational Site
city: Oviedo
country: Spain
facility: GSK Investigational Site
city: Pama de Mallorca
country: Spain
facility: GSK Investigational Site
city: Taipei
country: Taiwan
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Bristol
country: United Kingdom
facility: GSK Investigational Site
city: Cardiff
country: United Kingdom
facility: GSK Investigational Site
city: Liverpool
country: United Kingdom
facility: GSK Investigational Site
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Marty FM, Vidal-Puigserver J, Clark C, Gupta SK, Merino E, Garot D, Chapman MJ, Jacobs F, Rodriguez-Noriega E, Husa P, Shortino D, Watson HA, Yates PJ, Peppercorn AF. Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial. Lancet Respir Med. 2017 Feb;5(2):135-146. doi: 10.1016/S2213-2600(16)30435-0. Epub 2017 Jan 14.