| 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 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 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.
14. French and Korean subjects: the French or 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.
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.8.5 | 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 | No |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| 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 |
Print
