| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 19.0 |
| 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 |
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| 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 IV DNX twice daily given with oral oseltamivir compared to oral oseltamivir twice daily on time to clinical response (TTCR) |
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| E.2.2 | Secondary objectives of the trial |
- To assess the efficacy of treatment with IV DNX twice daily given with oral oseltamivir compared to oral oseltamivir twice daily on time to respiratory response (TTRR)
- To evaluate clinical measures of influenza illness following treatment with IV DNX twice daily given with oral oseltamivir compared to oral oseltamivir twice daily
- To characterize the safety and tolerability of IV DNX twice daily given with oral oseltamivir compared to oral oseltamivir twice daily
- To characterize the pharmacokinetics of IV DNX in subjects hospitalized for influenza |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
AGE
1. Adults 18 years (as per local laws) of age and older at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Presence of fever (≥38.0 °C [≥100.4 °F] by any route) at Baseline (enrollment) or history of fever/feverishness during the 48 hours prior.
3. O2 saturation <95% on room air by trans-cutaneous method OR need for any supplemental oxygenation (non-invasive ventilation, facemask, facetent, nasal canula, etc) or ventilator support (mechanical ventilation, bi-level positive airway pressure [BIPAP], continuous positive airway pressure [CPAP]) or increase in oxygen supplementation requirement of ≥2 liters 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 subject’s historical baseline oxygen saturation.
AND AT LEAST 2 out of the following 3:
- Respiratory rate >24 breaths per minute. For those subjects who require ventilator support or oxygen supplementation, this requirement is waived.
- Heart rate >100 bpm
- Systolic bp <90 mm Hg.
4. Severity of symptoms at enrollment:
- Less severe hospitalized subjects are those who (but not limited to):
- are hemodynamically stable;
- may require oxygenation with facemask, facetent, nasal canula, etc;
- may or may not have radiological signs of lower respiratory tract disease; or
- have exacerbation of underlying chronic disease, including asthma, chronic obstructive pulmonary disease (COPD), or other cardiovascular conditions not leading to hemodynamic compromise.
- Critically ill hospitalized subjects are those who (but not limited to):
- require CPAP, BIPAP, mechanical ventilation;
- have hemodynamic instability (with or without pressor support); or
- have central nervous system involvement (eg encephalopathy, encephalitis).
5. Presence of influenza that in the Investigator’s judgment requires hospitalization for treatment and supportive care
6. 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, nausea and vomiting.
7. A positive result from a rapid influenza test (provided by GSK) or other available, local laboratory diagnostic test;
8. Baseline renal criteria as follows:
Sentinel Cohorts:
- Normal renal function: Baseline creatinine clearance within normal reference ranges (≥80 mL/min) for the first approximately 30 subjects enrolled;
- Mild renal impairment: Baseline creatinine clearance of 50-79 mL/min for the next approximately 10 subjects enrolled into the sentinel cohort;
- Moderate renal impairment: Baseline creatinine clearance of 30-49 mL/min for the next approximately 10 subjects enrolled into the sentinel cohort.
Post-sentinel cohorts:
- Normal renal function, mild or moderate renal impairment: creatinine clearance >30mL/min.
9. Baseline Liver Function Tests as follows: (refer to the protocol P31 For further details)
SEX
10. Male or Female subjects could be eligible if :
Males:
Male subjects with female partners of child bearing potential must comply with the until at least 36 hours (five half-lives) after the last dose of study medication.
a. Vasectomy with documentation of azoospermia.
b. Male condom plus partner use of one of the contraceptive options below:
- Contraceptive subdermal implant
- Intrauterine device or intrauterine system
- Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] Injectable progestogen [Hatcher, 2007a]
- Contraceptive vaginal ring [Hatcher, 2007a]
- Percutaneous contraceptive patches [Hatcher, 2007a]
This is an all-inclusive list of those methods that meet the following GSK definition of
highly effective: having a failure rate of less than 1% per year when used consistently and
correctly and, when applicable, in accordance with the product label. For non-product
methods (e.g., male sterility), the investigator determines what is consistent and correct
use. The GSK definition is based on the definition provided by the ICH [ICH, M3 (R2)
2009].”
The investigator is responsible for ensuring that subjects understand how to properly use
these methods of contraception.
Females:
a. Non-reproductive potential defined as:
- Pre-menopausal females with one of the following:
- Documented tubal ligation
- Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
- Hysterectomy
- Documented Bilateral Oophorectomy
For further details and remainder of the inclusion criteria please refer to the protocol P32-33. |
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| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER FUNCTION AND QTc INTERVAL)
1. Subjects who, in the opinion of the investigator, are not likely to survive the next 48 hours beyond Baseline;
2. Immunosuppression, whether due to primary immunosuppressive conditions, such as history of inherited immunodeficiency syndromes, HIV infection, or secondary conditions, such as immunosuppressive medication, stem cell or solid organ transplantation, or malignancy;
3. Documented current liver disease (including Hepatitis A, B, or C), or known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones);
4. QTc Criteria: QTcB or QTcF >480 msec or >500 msec with bundle branch block;
5. For subjects enrolled in the sentinel cohorts: diabetes mellitus and chronic kidney disease;
6. Subjects who require dialysis, or are on renal replacement therapies;
7. Subjects who require extra corporeal membrane oxygenation (ECMO) at baseline (enrolled subjects who subsequently require ECMO may continue in the study)
8. Women who are pregnant as determined by a positive human chorionic gonadotrophin (hCG) ultrasensitive test prior to dosing or women who are breastfeeding;
CONCOMITANT MEDICATIONS
9. Subjects who received other treatments for influenza including vitaglutam, umifenovir, and neuraminidase inhibitors (oseltamivir, zanamivir, peramivir) for more than 72 hours during current acute illness;
10. Subjects who received any immunoglobulins within 6 months of screening or planned administration of any of these products during the treatment period.
11. Subjects treated with cytotoxic or immunosuppressive drugs within six months of study enrolment. Topical, intra-articularly injected, or inhaled glucocorticoids, topical calcineurin inhibitors or imiquimod are allowed.
RELEVANT HABITS
12. Known history of drug abuse within 6 months of study start.
CONTRAINDICATIONS
13. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
14. Absolute neutrophil count <1.0 Gi/L
15. Subjects who have participated in a clinical trial using an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint: Time to Clinical Response (composite)
• Hospital discharge
OR
• Normalization of:
o Temperature; and
o Oxygen saturation; and
o Respiratory status/Heart Rate/SBP (normalization of 2 out of these 3 parameters)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• Time to Respiratory Response defined as meeting at least one criterion below
- Return to pre-morbid oxygen requirement (subjects with chronic oxygen use), OR
- Return to no requirement of supplemental oxygen, OR
- Respiratory rate ≤24/min (without supplemental oxygen)
• Time to absence of fever
• Time to improved oxygen saturation
• Time to improved heart rate
• Time to improved SBP
• Proportion of subjects with clinical response over time
• Proportion of subjects with improved respiratory status over time
• Time to improvement of ventilation status: modality, frequencies and durations of invasive and non-invasive ventilator support, duration of oxygen supplementation.
• Length of stay in the ICU
• Frequency of ICU admission and readmission
• Length of stay in the hospital
• Rates of development of septic shock
• Frequency of antibiotic use
• Proportion of subjects with improvement in Ordinal scale of clinical efficacy over time :
- Death
- Mechanical vent
- In the ICU
- Non-ICU hospitalization
- Hospital discharge
• Frequency of adverse events (AEs) and serious adverse events (SAEs)
• Frequency of adverse events of special interest (AESIs)
• Change from baseline in clinical laboratory evaluations, and ECG parameters
• Standard pharmacokinetic parameters for IV danirixin (i.e. AUC, Cmax, Cavg).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | No |
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| 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 |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| United States |
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| 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
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| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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