Clinical Trials Register

Summary
EudraCT Number:	2010-021621-12
Sponsor's Protocol Code Number:	YM2010/00113/01
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-01-11
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Greece - EOF

A.2

EudraCT number

2010-021621-12

A.3

Full title of the trial

NAI114373: A Phase III international, randomized, doubleblind, 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.

A.3.2

Name or abbreviated title of the trial where available

N/A

A.4.1

Sponsor's protocol code number

YM2010/00113/01

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	GlaxoSmithKline Research & Development Ltd
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	IV Zanamivir
D.3.2	Product code	IV Zanamivir
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Zanamivir
D.3.9.1	CAS number	139110-80-8
D.3.9.2	Current sponsor code	GR121167X
D.3.9.3	Other descriptive name	Zanamivir
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Tamiflu 75 hard capsule
D.2.1.1.2	Name of the Marketing Authorisation holder	Hoffman-La Roche, Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Tamiflu
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	204255-11-8
D.3.9.3	Other descriptive name	OSELTAMIVIR PHOSPHATE
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	75
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

hospitalised adults and adolescents with influenza

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	12.1
E.1.2	Level	LLT
E.1.2	Classification code	10022000
E.1.2	Term	Influenza

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy of treatment with 300 mg or 600 mg of intravenous (IV) zanamivir twice daily compared to 75 mg of oral oseltamivir twice daily on time to clinical response (TTCR).
Clinical response is defined as resolution of at least 4 of the 5 vital signs described below within the respective resolution criteria, maintained for at least 24 hours, or hospital discharge, whichever comes first: Please refer to page 21 of Protocol

E.2.2

Secondary objectives of the trial

•To assess reduction in viral load from nasopharyngeal swabs (and lower respiratory tract samples, if available) following treatment with 300 mg or 600 mg of IV zanamivir twice daily compared to 75 mg oral oseltamivir twice daily.
•To evaluate clinical measures of influenza illness following treatment with 300 mg or 600 mg IV zanamivir twice daily compared to 75 mg oral oseltamivir twice daily using a variety of measures including improvement in Katz ADL score and ADL activities, improvement in level of activity, duration and severity of influenza symptoms, duration of hospital stay, duration of ICU stay, complications of influenza, associated antibiotic use, modality and duration of invasive and non-invasive ventilator support, duration and quantity of oxygen supplementation and overall and disease specific mortality.

For other secondary objectives, please see Protocol pg 22

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects eligible for enrolment in the study must meet all of the following criteria:
1.Male or female aged greater than or equal16 years (greater than or equal 18 years where required by local regualtory authorities or IRB/IEC); a female is eligible to enter and participate in the study if she is:
a.of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal); or,
b.of child-bearing potential, has a negative pregnancy test at Baseline, and agrees to one of the following methods for avoidance of pregnancy during the study and until the Post-Treatment +28 Days Follow-up Assessment:
•Abstinence; or,
•Oral contraceptive, either combined or progestogen alone; or,
•Injectable progestogen; or,
•Implants of levonorgestrel; or,
•Estrogenic vaginal ring; or,
•Percutaneous contraceptive patches; or
•Intrauterine device (IUD) or intrauterine system (IUS) showing that the expected failure rate is less than 1% per year as stated in the IUD or IUS Product Label; or,
•Has a male partner who is sterilized; or,
•Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository).
2.Vital signs criteria defined as 3 or more of the following at Baseline:
•Presence of fever [oral temperature of ≥38°C (≥100.4°F), rectal, tympanic of ≥38.5°C (≥101.3°F), or axilla ≥37.4°C (≥99.3°F)] at Baseline. However, this requirement is waived if:
i.The subject has a history of fever within the 24 hours prior to Baseline and has been administered any antipyretic(s) in the 24 hours prior to Baseline; or,
ii.The subject has no history of documented fever as defined above, but reports a symptom of feverishness at some time during the 48 hours prior to Baseline.
AND at least 2 out of the following 4:
•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.
•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.
3.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.
4.Clinical symptoms of influenza with positive influenza diagnostic test result.
•Subjects who have 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.
OR
Strong suspicion of influenza ilness based on clinical symptoms and local surveillance information.
Subjects with a negative RAT or pending other influenza laboratory test result may be enrolled.
5.Subjects/legal ly accepatable representatvi (LAR) of minors and 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 (or included as permitted by local regulatory authorities, IRB/IECs or local laws).
6.Severity of any medical illness that, in the Investigator’s judgement, justifies hospitalization of the subject for treatment and supportive care
7.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
Subjects who meet the above criteria are considered eligible for the study. This includes, but is not limited to, subjects who are intubated/mechanically ventilated, immunocompromised, HIV positive or have renal impairment requiring approved renal replacement therapies.

E.4

Principal exclusion criteria

Subjects meeting any of the following criteria must not be enrolled in the study:
1.Subjects who have taken more than a total of 3 days (6 doses) of approved anti-influenza therapy (i.e. oral oseltamivir, oral inhaled zanamivir, oral amantadine, oral rimantadine, or oral ribavirin) in the period from onset of symptoms and prior to enrolment.
2.Subjects who, in the opinion of the investigator, are not likely to survive beyond 48 hours from Baseline.
3.Subjects who are considered to require concurrent therapy with another influenza antiviral medication.
4.Subjects who are known or suspected to be hypersensitive to any component of the study medications.
5.Subjects with creatinine clearance <10 mL/min who are not being treated with continuous renal replacement therapy (CRRT).
6.Subjects who require Extra Corporeal Membrane Oxygenation (ECMO) at Baseline (enrolled subject who subsequently require ECMO may continue in the study).
7.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 (CVVH, CVVHD, CVVHDF, SLED, SCUF, CAVH, CAVHD, CAVHDF) as are sustained or extended techniques (SLED, SLEDD, EDD).
8.Liver toxicity criteria based on local laboratory results obtained within 24 hours of Baseline:
•ALT or AST ≥3xULN and bilirubin ≥2xULN
•ALT ≥5xULN
9.Underlying chronic liver disease with evidence of severe liver impairment (Child-Pugh Class C).
10.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.
11.Females who are pregnant (positive urine or serum pregnancy test at Baseline) or are breastfeeding.
12.Treatment with investigational parenteral anti-influenza drugs (IV peramivir, IV zanamivir or IV oseltamivir) in the 4 weeks prior to Baseline.
13.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
14.French and Korean subjects: the French and Korean subject has participated in any study using an investigational drug during the previous 30 days. This criterion may also apply in other countries if required by local regulatory authorities or IRB/IECs.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the time to clinical response in subjects with confirmed influenza treated with 300 mg or 600 mg IV zanamivir compared with 75 mg oral oseltamivir.
Clinical response is defined as resolution of at least 4 of the 5 signs described below within the respective resolution criteria, maintained for at least 24 hours, or hospital discharge, whichever occurs first:
Please refer to page 54 of Protocol

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

double-dummy

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Tamiflu 75 mg

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LSLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

It is anticipated that many subjects eligible for this study will not be able to give consent themselves due to their medical condition. In such cases, and if allowed by applicable local laws, consent may be obtained from LAR. Refer pg 77 of protocol

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

154

F.4.2.2

In the whole clinical trial

462

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

No post-study medication is provided as part of this protocol.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-01-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-12-21

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-03-18

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