Clinical Trials Register

Summary
EudraCT Number:	2016-002688-32
Sponsor's Protocol Code Number:	1602T0832
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-09-07
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Belgium - FPS Health-DGM

A.2

EudraCT number

2016-002688-32

A.3

Full title of the trial

A Phase 3, Multicenter, Randomized, Double-blind Study of a Single Dose of S-033188 Compared with Placebo or Oseltamivir 75 mg Twice Daily for 5 Days in Patients with Influenza at High Risk of Influenza Complications

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A clinical trial which compares the effectiveness and safety of a not yet approved drug, called S-033188, versus placebo, and versus an approved drug (Oseltamivir) for 5 Days in Patients with Influenza at High Risk of Influenza Complications

A.4.1

Sponsor's protocol code number

1602T0832

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Shionogi 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	Shionogi Ltd.
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Shionogi & Co. Ltd
B.5.2	Functional name of contact point	Corporate Communications Department
B.5.3	Address:
B.5.3.1	Street Address	1-8, Doshomachi 3-chome
B.5.3.2	Town/ city	Chuo-ku, Osaka,
B.5.3.3	Post code	541-0045
B.5.3.4	Country	Japan
B.5.4	Telephone number	+8166209 7885
B.5.6	E-mail	shionogiclintrials-admin@shionogi.co.jp

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	S-033188
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not yet assigned
D.3.9.1	CAS number	1830312-72-5
D.3.9.2	Current sponsor code	S-033188
D.3.9.3	Other descriptive name	S-033188
D.3.9.4	EV Substance Code	SUB182710
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	20
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)	No
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	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
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	No
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® Hard Capsules 75 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	oseltamivir
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OSELTAMIVIR
D.3.9.1	CAS number	196618-13-0
D.3.9.4	EV Substance Code	SUB03553MIG
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)	No
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	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
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	No
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	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
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

Influenza

E.1.1.1

Medical condition in easily understood language

Influenza

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	100000005073

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
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	100000015765

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
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	100000015765

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 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

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.

E.2.3

Trial contains a sub-study

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

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.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint will be the time to improvement of influenza symptoms.

E.5.1.1

Timepoint(s) of evaluation of this end point

Throughout study duration

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).

E.5.2.1

Timepoint(s) of evaluation of this end point

Throughout study duration

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

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

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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

E.8.1.6

Cross over

E.8.1.7

Other

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

E.8.2.4

Number of treatment arms in the trial

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

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

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

LVLS

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

431

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.1.1.6.1

Number of subjects for this age range:

431

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

863

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

863

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

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

persons in nursing homes

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

101

F.4.2.2

In the whole clinical trial

2157

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)

None

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

2017-09-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-05-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-04-20

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials