| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| hospitalised adults and adolescents with influenza |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10022000 |
| E.1.2 | Term | Influenza |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess the efficacy of treatment with 600 mg of intravenous (IV)
zanamivir twice daily compared to 75 mg of oral oseltamivir twice daily,
and 600 mg IV zanamivir compared to 300 mg IV zanamivir twice daily
on time to clinical response (TTCR). |
|
| E.2.2 | Secondary objectives of the trial |
-To assess the efficacy of treatment with 600 mg IV zanamivir twice
daily compared to 75 mg of oral oseltamivir twice daily, and 600 mg IV
zanamivir compared to 300 mg IV zanamivir twice daily as measured by
the combined analysis of TTCR and time to improvement in respiratory
status (RS).
- To assess mortality following treatment with 600 mg IV zanamivir
twice daily compared to 75 mg oral oseltamivir twice daily, and 600 mg
IV zanamivir compared to 300 mg IV zanamivir twice daily in the
treatment of hospitalized adult and adolescent subjects with influenza
infection.
- To assess reduction in viral load from nasopharyngeal swabs (and
lower respiratory tract samples, if available) following treatment with
600 mg IV zanamivir twice daily compared to 75 mg oral oseltamivir
twice daily, and 600 mg IV zanamivir compared to 300 mg IV zanamivir
twice daily.
For other secondary objectives, please see Protocol pg 25
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1.Male or female aged ≥ 16 years; (≥ 18 years where required by local
regulatory authorities or IRB/IECs); 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 at Baseline defined as:
- Presence of fever [oral temperature of ≥38°C (≥100.4°F), rectal/core,
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,
with or without administration of antipyretic(s) 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:
- 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 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 illness based on clinical symptoms and
local
surveillance information.
- Subjects with a negative RAT or pending other influenza laboratory test
may be enrolled.
5. 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 (LAR) willing and able to give written
informed consent on behalf of the subject to participate in the study for
minors, unconscious adults, and those incapable of consenting
themselves due to their medical condition (e.g. too weak or debilitated,
severe shortness of breath), or included
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 antiinfluenza therapy (i.e. oral oseltamivir, oral inhaled
zanamivir, oral amantadine, oral rimantadine, oral ribavirin, or IV
peramivir, where approved) 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).
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.
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. Exclusion criterion #13 removed in Protocol Amendment 02.
|
|
| 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.
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 see protocol page 65
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- The combined analysis of TTCR and time to improvement in RS.
- Mortality rate at Day 14, Day 28 and end of study (all cause and
attributable mortality).
- Change from Baseline in Katz ADL score and each ADL activity between
treatment arms at Day 5/6, and Day 10/11 and Day 14 if treatment is
extended beyond 5 days, and end of study (Post- Treatment +28 Days).
- Time to return to pre-morbid functional status as measured by the Katz
ADL score and each ADL activity.
- Proportion of subjects in each treatment arm who have returned to
pre-morbid functional status by the Katz ADL score and each ADL activity
at the end of study (Post-Treatment +28 Days).
-The combined analysis of TTCR and time to improvement in RS.
More secondary endpoints on protocol page 66
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 57 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| China |
| Colombia |
| Czech Republic |
| 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 |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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