Clinical Trials Register

Summary
EudraCT Number:	2018-001416-30
Sponsor's Protocol Code Number:	CP40617
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-12-07
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

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A. Protocol Information

A.1

Member State Concerned

Sweden - MPA

A.2

EudraCT number

2018-001416-30

A.3

Full title of the trial

A PHASE III, RANDOMIZED, DOUBLE-BLIND PLACEBO-CONTROLLED, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF BALOXAVIR MARBOXIL IN COMBINATION WITH
STANDARD-OF-CARE NEURAMINIDASE INHIBITOR IN HOSPITALIZED PATIENTS WITH SEVERE INFLUENZA

A.3.1

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

A Study to Evaluate the Efficacy and Safety of Baloxavir Marboxil in Combination with Standard of Care Neuraminidase Inhibitor in Hospitalized Patients with Severe Influenza

A.4.1

Sponsor's protocol code number

CP40617

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	F. Hoffmann-La Roche Ltd
B.1.3.4	Country	Switzerland
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	F. Hoffmann-La Roche Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F. Hoffmann-La Roche Ltd
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.6	E-mail	global.rochegenentechtrials@roche.com

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	Baloxavir marboxil
D.3.2	Product code	RO7191686/F04
D.3.4	Pharmaceutical form	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	BALOXAVIR MARBOXIL
D.3.9.2	Current sponsor code	RO7191686
D.3.9.3	Other descriptive name	S-033188
D.3.9.4	EV Substance Code	SUB190816
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	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	Baloxavir marboxil
D.3.2	Product code	RO7191686/F08
D.3.4	Pharmaceutical form	Granules
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	BALOXAVIR MARBOXIL
D.3.9.2	Current sponsor code	RO7191686
D.3.9.3	Other descriptive name	S-033188
D.3.9.4	EV Substance Code	SUB190816
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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	Tablet
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	Granules
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, commonly known as "the flu", is an infectious respiratory disease caused by influenza viruses

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	LLT
E.1.2	Classification code	10016790
E.1.2	Term	Flu
E.1.2	System Organ Class	100000004862

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	10022001
E.1.2	Term	Influenza (epidemic)
E.1.2	System Organ Class	100000004862

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

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

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 clinical efficacy of baloxavir marboxil plus a standard-of-care (SOC) neuraminidase inhibitor (NAI) compared with matching placebo plus a SOC NAI based on time to clinical improvement

E.2.2

Secondary objectives of the trial

To evaluate
• the clinical efficacy of baloxavir marboxil plus a SOC NAI compared with matching placebo plus a SOC NAI based on response rates of the 6-point ordinal scale at Day 7, time to clinical response, incidence and duration of mechanical ventilation, intensive care unit stay, incidence of post-treatment influenza-related complications, time to clinical failure, hospital discharge, National Early Warning Score (NEWS) 2 of <= 2 maintained for 24 hours, mortality rate at Day 7 and 28
• the antiviral activity of baloxavir marboxil plus a SOC NAI compared with matching placebo plus a SOC NAI
• the polymorphic and treatment-emergent amino acid substitutions in the PA, PB1, PB2, and NA genes and drug susceptibility in patients with evaluable virus
• the safety of baloxavir marboxil plus a SOC NAI compared with matching placebo plus a SOC NAI in hospitalized patients with influenza
• the single- and multiple dose pharmacokinetics of baloxavir

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Adult patients: Signed informed consent by any patient capable of giving consent, or, where the patient is not capable of giving consent, by his or her legal/authorized representative
- Adolescent patients not able to legally consent: written informed consent for study participation is obtained from patient’s parents or legal guardian, with assent as appropriate by the patient, depending on the patient’s level of understanding and capability to provide assent
- Age >= 12 years at the time of signing the Informed Consent Form/Assent Form
- Ability to comply with the study protocol, in the investigator’s judgment
- Patients who require hospitalization for severe influenza or acquire influenza during hospitalization, the severity of which requires an extension of hospitalization
- Diagnosis of influenza A and/or B by a positive Rapid Influenza Diagnostic Test (RIDT) or reverse transcriptase-polymerase chain reaction (RT-PCR) A patient with a negative RIDT may be enrolled if influenza is suspected based on local surveillance data or if the patient reports contact with a known case of influenza within the prior 7 days
- The time interval between the onset of symptoms and randomization is within 96 hours
- A score of >= 4 based on the NEWS2
- Patients will require objective criteria of seriousness defined by at least one of the following criteria:
• Requires ventilation or supplemental oxygen to support respiration
• Has a complication related to influenza that requires hospitalization
- For women of childbearing potential: Agreement to remain abstinent (refrain from heterosexual intercourse) women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 28 days after the last dose of study treatment. Hormonal contraceptive methods must be supplemented by a barrier method

E.4

Principal exclusion criteria

- Patients who have received more than 48 hours of antiviral treatment for the current influenza infection prior to screening
- Patients who have received baloxavir marboxil for the current influenza infection
- Known contraindication to neuraminidase inhibitors
- Known hypersensitivity to baloxavir marboxil or the drug product excipients
- Patients hospitalized for exclusively social reasons (e.g., lack of caregivers at home)
- Patients expected to die or be discharged within 48 hours, according to the investigator’s judgement
- Patients weighing <40 kg
- Patients with known severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2) or receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis
- Patients with any of the following laboratory abnormalities detected within 24 hours prior to or during screening (according to local laboratory reference ranges):
• ALT or AST level >5 times the upper limit of normal (ULN)
OR
• ALT or AST >3 times the ULN and total bilirubin level >2 times the ULN
- Pregnant or breastfeeding, or positive pregnancy test in a predose examination, or intending to become pregnant during the study or within 28 days after the last dose of study treatment
- Exposure to an investigational drug within 5 half-lives or 30 days (whichever is longer) of randomization
- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in and completion of the study
- Known hypersensitivity to baloxavir marboxil or the drug product excipients

E.5 End points

E.5.1

Primary end point(s)

1. Time to clinical improvement (defined as time to hospital discharge OR time to NEWS2 of less than or equal to 2 maintained for 24 hours)

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Up to Day 35

E.5.2

Secondary end point(s)

Key secondary efficacy:
1. Response rates of the 6-point ordinal scale at Day 7
2. Time to clinical response based on temperature ranges, oxygen saturation, respiratory status, heart
rate, and hospitalization Status

Secondary efficacy:
3. Incidence of mechanical ventilation
4. Duration of mechanical ventilation
5. Incidence of Intensive Care Unit stay
6. Duration of Intensive Care Unit stay
7. Time to clinical failure
8. Time to hospital discharge
9. Incidence of post-treatment influenza-related complications
10. Mortality rate at Day 7
11. Mortality rate at Day 28
12. Time to NEWS2 of <= 2 maintained for 24 hours

Virology
13. Time to cessation of viral shedding by virus titer
14. Time to cessation of viral shedding by RT-PCR
15. Change from baseline in influenza virus titer and in the amount of virus RNA (RT-PCR) at each time point
16. Proportion of patients with positive influenza virus titer and proportion of patients positive by RT-PCR at each time point
17. Area under the concentration-time curve (AUC), in virus titer and in the amount of virus RNA (RT PCR)
18. Polymorphic and treatment-emergent amino acid substitutions in the PA, PB1, PB2, and NA genes
19. Drug susceptibility in patients with evaluable virus
Safety
20. Compare the incidence and severity of adverse event (AE)s and serious AEs
21. Incidence of AEs leading to discontinuation
22. Proportion of patients with any post-treatment ALT and AST above baseline and >3 × ULN, >5 × ULN, >10 × ULN
PK
23. Plasma concentrations of baloxavir (active metabolite) at specified timepoints
24. Baloxavir concentration at pre-dose and at 24 hour after each dose of baloxavir marboxil (C24) (all patients)
25. Total drug exposure area under the curve (AUC), maximum plasma concentration (Cmax) and Half-life (t1/2) area under the concentration–time curve from time 0 to infinity (AUCinf) and clearance at steady state (CL) of baloxavir (only for patients undergoing sequential PK sampling)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. At Day 7
2-9. Up to Day 35
10. At Day 7
11. At Day 28
12-22. Up to Day 35
23-25. Up to Day 35

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

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

Yes

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)

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

Argentina

Australia

Belgium

Brazil

Bulgaria

Canada

Czech Republic

Estonia

France

Germany

Hong Kong

Hungary

Israel

Japan

Korea, Republic of

Mexico

Netherlands

New Zealand

Peru

Romania

Serbia

Singapore

Spain

Sweden

Turkey

Ukraine

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

The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the date at which the last data point required for statistical analysis or safety follow-up is received from the last patient, whichever occurs later.

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

E.8.9.2

In all countries concerned by the trial days

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:

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:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

191

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

165

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Adult patients not capable of giving consent;
Adolescent patients (age more than or equal to 12 years) not able to legally consent

F.3.3.7

Others

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

180

F.4.2.2

In the whole clinical trial

366

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)

Currently, the Sponsor does not have any plans to provide the Roche IMP (baloxavir marboxil) or any other study treatments or interventions to patients who have completed the study.

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

2018-12-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-03-16

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