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

NCT ID: NCT01231620

Last Updated: 2018-10-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 626 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-01-15
• Study Completion Date: 2015-03-18

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.

Conditions

Influenza, Human

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Intravenous (IV) Zanamivir 300mg Twice Daily

300mg of IV zanamivir infusion twice daily plus oral oseltamivir placebo twice daily

Group Type: EXPERIMENTAL

Zanamivir

Intervention Type: DRUG

Zanamivir aqueous solution, 10 mg/mL, will be provided as a single use, sterile clear, colorless preparation in 20 mL clear glass vials.

Placebo to match oseltamivir

Intervention Type: DRUG

Placebo to match oral oseltamivir will be provided as capsules with a common excipient of appropriate quality.

Intravenous (IV) Zanamivir 600mg Twice Daily

600mg of IV zanamivir infusion twice daily plus oral oseltamivir placebo twice daily

Group Type: EXPERIMENTAL

Zanamivir

Intervention Type: DRUG

Zanamivir aqueous solution, 10 mg/mL, will be provided as a single use, sterile clear, colorless preparation in 20 mL clear glass vials.

Placebo to match oseltamivir

Intervention Type: DRUG

Placebo to match oral oseltamivir will be provided as capsules with a common excipient of appropriate quality.

Oral Oseltamivir 75mg Twice Daily

75mg oral oseltamivir twice daily plus intravenous placebo zanamivir twice daily

Group Type: ACTIVE_COMPARATOR

Placebo to match zanamivir

Intervention Type: DRUG

Placebo to match IV zanamivir will be provided as a normal saline solution of a matched volume.

Oseltamivir

Intervention Type: DRUG

Oseltamivir will be provided as over-encapsulated 75 mg capsules.

Interventions

Zanamivir

Zanamivir aqueous solution, 10 mg/mL, will be provided as a single use, sterile clear, colorless preparation in 20 mL clear glass vials.

Intervention Type: DRUG

Placebo to match zanamivir

Placebo to match IV zanamivir will be provided as a normal saline solution of a matched volume.

Intervention Type: DRUG

Oseltamivir

Oseltamivir will be provided as over-encapsulated 75 mg capsules.

Intervention Type: DRUG

Placebo to match oseltamivir

Placebo to match oral oseltamivir will be provided as capsules with a common excipient of appropriate quality.

Intervention Type: DRUG

Other Intervention Names

Relenza; Tamiflu

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.

• Minimum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Birmingham, Alabama, United States

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Phoenix, Arizona, United States

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Chula Vista, California, United States

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Escondido, California, United States

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Fullerton, California, United States

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La Jolla, California, United States

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La Mesa, California, United States

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Oceanside, California, United States

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Aurora, Colorado, United States

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Stamford, Connecticut, United States

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Orlando, Florida, United States

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Sarasota, Florida, United States

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Sunrise, Florida, United States

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Atlanta, Georgia, United States

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Augusta, Georgia, United States

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Idaho Falls, Idaho, United States

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Chicago, Illinois, United States

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Oak Park, Illinois, United States

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Peoria, Illinois, United States

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Council Bluffs, Iowa, United States

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Topeka, Kansas, United States

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Louisville, Kentucky, United States

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Boston, Massachusetts, United States

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Royal Oak, Michigan, United States

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Troy, Michigan, United States

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St Louis, Missouri, United States

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Missoula, Montana, United States

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Las Vegas, Nevada, United States

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Valhalla, New York, United States

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Asheville, North Carolina, United States

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Chapel Hill, North Carolina, United States

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Bismarck, North Dakota, United States

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Cleveland, Ohio, United States

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Columbus, Ohio, United States

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Toledo, Ohio, United States

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Bethlehem, Pennsylvania, United States

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Philadelphia, Pennsylvania, United States

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Houston, Texas, United States

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Roanoke, Virginia, United States

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Marshfield, Wisconsin, United States

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Westmead, New South Wales, Australia

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Herston, Queensland, Australia

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Adelaide, South Australia, Australia

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Bedford Park, South Australia, Australia

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Clayton, Victoria, Australia

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Heidelberg, Victoria, Australia

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Melbourne, Victoria, Australia

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Melbourne, Victoria, Australia

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Perth, Western Australia, Australia

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Brussels, , Belgium

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Brussels, , Belgium

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Leuven, , Belgium

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Liège, , Belgium

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Rio de Janeiro, , Brazil

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São Paulo, , Brazil

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Calgary, Alberta, Canada

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Calgary, Alberta, Canada

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Halifax, Nova Scotia, Canada

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Hamilton, Ontario, Canada

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Toronto, Ontario, Canada

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Chicoutimi, Quebec, Canada

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Montreal, Quebec, Canada

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Montreal, Quebec, Canada

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Trois-Rivières, Quebec, Canada

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Haikou, Hainan, China

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Changsha, Hunan, China

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Nanchang, Jiangxi, China

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Changchun, Jilin, China

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Xi'an, Shaanxi, China

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Hangzhou, Zhejiang, China

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Beijing, , China

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Beijing, , China

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Chengdu, , China

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Chongqing, , China

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Guangzhou, , China

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Hangzhou, , China

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Shanghai, , China

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Tianjin, , China

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Bogotá, , Colombia

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Brno, , Czechia

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Brno - Bohunice, , Czechia

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Hradec Králové, , Czechia

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Prague, , Czechia

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Aarhus N, , Denmark

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Hvidovre, , Denmark

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Odense C, , Denmark

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Dijon, , France

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Limoges, , France

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Nîmes, , France

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Orléans, , France

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Poitiers, , France

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Tours, , France

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Ulm, Baden-Wurttemberg, Germany

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Erlangen, Bavaria, Germany

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Regensburg, Bavaria, Germany

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Hanover, Lower Saxony, Germany

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Homburg, Saarland, Germany

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Chaïdári, , Greece

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Goudi, Athens, , Greece

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Kwun Tong, , Hong Kong

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Shatin, , Hong Kong

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Tuenmen, , Hong Kong

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Debrecen, , Hungary

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Kaposvár, , Hungary

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Miskolc, , Hungary

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Székesfehérvár, , Hungary

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Szombathely, , Hungary

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Bangalore, , India

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Civil Lines, , India

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Lucknow, , India

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Lucknow, , India

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Pune, , India

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Pune, , India

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Trivandrum, , India

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Guadalajara, Jalisco, Mexico

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San Nicolás de los Garza, Nuevo León, Mexico

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Cuautitlán, Estado de México, State of Mexico, Mexico

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Aguascalientes, , Mexico

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Chihuahua City, , Mexico

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Nijmegen, , Netherlands

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Auckland, , New Zealand

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Auckland, , New Zealand

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Auckland, , New Zealand

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Christchurch, , New Zealand

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Hamilton, , New Zealand

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Hastings, , New Zealand

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Newtown, , New Zealand

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Bergen, , Norway

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Trondheim, , Norway

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Chorzów, , Poland

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Dębica, , Poland

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Trzebnica, , Poland

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Warsaw, , Poland

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Barnaul, , Russia

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Barnaul, , Russia

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Saint Petersburg, , Russia

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Saint Petersburg, , Russia

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Smolensk, , Russia

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Bratislava, , Slovakia

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Martin, , Slovakia

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Middelburg, Mpumalanga, South Africa

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Bellville, , South Africa

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Die Wilgers, , South Africa

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Les Marais, , South Africa

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Panorama, , South Africa

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Worcester, , South Africa

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Guro Gu, , South Korea

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Gyeonggi-do, , South Korea

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Kangwon-do, , South Korea

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Seoul, , South Korea

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Seoul, , South Korea

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Alicante, , Spain

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Badalona, , Spain

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Barcelona, , Spain

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Granada, , Spain

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Granada, , Spain

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L'Hospitalet de Llobregat, , Spain

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Madrid, , Spain

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Madrid, , Spain

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Madrid, , Spain

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Murcia, , Spain

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Oviedo, , Spain

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Pama de Mallorca, , Spain

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Taipei, , Taiwan

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Bangkok, , Thailand

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Bangkok, , Thailand

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Bristol, , United Kingdom

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Cardiff, , United Kingdom

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Liverpool, , United Kingdom

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Manchester, , United Kingdom

Countries

United States; Australia; Belgium; Brazil; Canada; China; Colombia; Czechia; Denmark; France; Germany; Greece; Hong Kong; Hungary; India; Mexico; Netherlands; New Zealand; Norway; Poland; Russia; Slovakia; South Africa; South Korea; Spain; Taiwan; Thailand; United Kingdom

References

van Duijnhoven W, Van Dromme I, Haesendonckx S, Witek J, Leopold L. The Hospital Recovery Scale: A clinically useful endpoint in patients hospitalized with influenza. Contemp Clin Trials. 2022 Dec;123:106952. doi: 10.1016/j.cct.2022.106952. Epub 2022 Oct 3.

Reference Type: DERIVED

PMID: 36202198 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28094141 (View on PubMed)

Study Documents

Document Type: Annotated Case Report Form

For additional information about this study please refer to the GSK Clinical Study Register

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Document Type: Statistical Analysis Plan

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Document Type: Clinical Study Report

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Document Type: Individual Participant Data Set

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Document Type: Dataset Specification

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Document Type: Informed Consent Form

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Document Type: Study Protocol

For additional information about this study please refer to the GSK Clinical Study Register

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Other Identifiers

114373

Identifier Type: -

Identifier Source: org_study_id