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 | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10022005 |
E.1.2 | Term | Influenza viral infections |
E.1.2 | System Organ Class | 100000004862 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10022002 |
E.1.2 | Term | Influenza A virus infection |
E.1.2 | System Organ Class | 100000004862 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10022003 |
E.1.2 | Term | Influenza B virus infection |
E.1.2 | System Organ Class | 100000004862 |
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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 evaluate the efficacy of a single, oral dose of S-033188 compared with placebo by measuring the time to improvement of influenza symptoms in patients with influenza |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of a single, oral dose of S-033188 compared with oseltamivir 75 mg twice daily (BID) for 5 days by measuring the time to improvement of influenza symptoms in patients with influenza. • To evaluate the efficacy of a single, oral dose of S-033188 compared with placebo by measuring the secondary endpoints in patients with influenza. • To evaluate the efficacy of a single, oral dose of S-033188 compared with oseltamivir 75 mg BID for 5 days by measuring the secondary endpoints in patients with influenza. • To evaluate the polymorphic and treatment-emergent amino acid substitutions in the polymerase acidic protein (PA) gene and drug susceptibility in patients with evaluable virus. • To compare the safety and tolerability of a single dose of S-033188 with placebo. • To compare the safety and tolerability of a single dose of S-033188 with oseltamivir 75 mg BID for 5 days. •Further objectives are listed in the enclosed protocol.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients who fulfill all of the following criteria will be included in the study: 1.Patients or their legal guardians who provide written informed consent to participate in the study on a voluntary basis. For adolescent patients, informed consent/assent of voluntary participation should be obtained in accordance with local requirements. 2.Male or female patients ≥ 12 years at the time of signing the informed consent/assent form. 3.Patients with a diagnosis of influenza confirmed by all of the following: a.Fever ≥ 38ºC (axillary) during the predose examinations or > 4 hours after dosing of antipyretics if they were taken b.At least 1 each of the following general and respiratory symptoms associated with influenza (excluding those that are chronic and existed in the 30 days prior to the influenza episode) is present with a severity of moderate or greater: i.General symptoms (headache, feverishness or chills, muscle or joint pain, or fatigue) ii.Respiratory symptoms (cough, sore throat, or nasal congestion) 4.The time interval between the onset of symptoms and the predose examinations (Screening) is 48 hours or less. The onset of symptoms is defined as either: a.Time of the first increase in body temperature (an increase of at least 1ºC from normal body temperature) b.Time when the patient experiences at least 1 new general or respiratory symptom 5.If a women of childbearing potential, agrees to use a highly effective method of contraception for 3 months after the first dose of S 033188 or oseltamivir 6.Patients will be considered at high risk of influenza complications due to the presence of at least 1 of the following inclusion criteria: a.Asthma or chronic lung disease (such as chronic obstructive pulmonary disease or cystic fibrosis) b.Endocrine disorders (including diabetes mellitus) c.Residents of long-term care facilities (eg, nursing homes) d.Compromised immune system (including patients receiving corticosteroids not exceeding 20 mg of prednisolone or equivalent, and patients being treated for human immunodeficiency virus (HIV) infection with a CD4 count > 350 cells/mm3 within the last 6 months) e.Neurological and neurodevelopmental disorders (including disorders of the brain, spinal cord, peripheral nerve, and muscle, eg, cerebral palsy, epilepsy [seizure disorders], stroke, muscular dystrophy, or spinal cord injury) f.Heart disease (such as congenital heart disease, congestive heart failure, or coronary artery disease), excluding hypertension without any other heart related symptoms g.Adults aged ≥ 65 years h.American Indians and Alaskan Natives i.Blood disorders (such as sickle cell disease) j.Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders) k.Morbid obesity (body mass index ≥ 40) l.Women who are within 2 weeks postpartum and are not breastfeeding |
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E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria will be excluded from the study: 1.Patients with severe influenza virus infection requiring inpatient treatment. 2.Patients with known allergy to oseltamivir (Tamiflu®). 3.Patients unable to swallow tablets or capsules. 4.Patients who have previously received S-033188. 5.Patients weighing < 40 kg. 6.Patients who have been exposed to an investigational drug within 30 days prior to the predose examinations. 7.Women who are pregnant, breastfeeding, or have a positive pregnancy test at the predose examinations. The following female patients who have documentation of either a or b below do not need to undergo a pregnancy test at the predose examinations: a.Postmenopausal women (defined as cessation of regular menstrual periods for 2 years or more and confirmed by a follicle-stimulating hormone test) b.Women who are surgically sterile by hysterectomy, bilateral oophorectomy, or tubal ligation 8.Patients with concurrent infections at the predose examinations requiring systemic antimicrobial therapy. 9.Patients with liver disease associated with hepatic impairment. 10.Patients with cancer within the last 5 years (unless nonmelanoma skin cancer). 11.Patients with untreated HIV infection or treated HIV infection with an unknown CD4 count or a CD4 count below 350 cells/mm3 in the last 6 months. 12.Patients with immunosuppression following organ or bone marrow transplants. 13.Patients exceeding 20 mg of prednisolone or equivalent dose of chronic systemic corticosteroids. 14.Patients who have received peramivir, laninamivir, oseltamivir, zanamivir, rimantadine, umifenovir or amantadine within 30 days prior to the predose examinations. 15.Patients who have received an investigational monoclonal antibody for a viral disease in the last year. 16.Patients with current creatinine clearance ≤ 60 mL/min (≤ 30 mL/min in Japan). 17.Patients with hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose intolerance. 18. Pediatric patients in countries where national legislation prohibits the conduct of studies with a placebo arm in pediatrics. 19. Patients who, in the opinion of the investigator, would be unlikely to comply with required study visits, self-assessments, and interventions. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the time to improvement of influenza symptoms. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout study duration |
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E.5.2 | Secondary end point(s) |
● Proportion of patients positive for virus titer and proportion of patients positive by RT-PCR at each time point ● Change from baseline in virus titer and in the amount of virus (RT-PCR) at each time point ● AUC adjusted by baseline in virus titer and in the amount of virus RNA (RT-PCR) ● Time to cessation of viral shedding by virus titer and by RT-PCR ● Proportion of patients whose symptoms has been alleviated at each time point ● Time to alleviation of symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) ● Time to improvement in the 4 systemic symptoms (headache, feverishness/chills, muscle/joint pain, and fatigue) ● Time to improvement in the 3 respiratory symptoms (cough, nasal congestion, and sore throat) ● Time to resolution of fever ● Proportion of patients reporting normal temperature at each time point ● Body temperature at each time point ● Time to improvement of each influenza symptom ● Time to return to preinfluenza health status ● Requirement for systemic antibiotics for infections secondary to influenza infection ● Incidence of influenza-related complications (hospitalization, death, sinusitis, bronchitis, otitis media, and radiologically confirmed pneumonia). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout study duration |
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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 | Yes |
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 | No |
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) | Yes |
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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Australia |
Bulgaria |
Czech Republic |
Germany |
Hungary |
Japan |
Korea, Republic of |
Latvia |
Moldova, Republic of |
New Zealand |
Philippines |
Poland |
Romania |
Singapore |
South Africa |
Spain |
Taiwan |
Ukraine |
United Kingdom |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |