Clinical Trial Results:
A phase 3 randomized, double-blind, placebo-controlled study to confirm the efficacy of a single dose of baloxavir marboxil in the prevention of influenza virus infection
Summary
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EudraCT number |
2020-000696-20 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
25 Mar 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Jul 2020
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First version publication date |
12 Jul 2020
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
1719T0834
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Shionogi & Co., Ltd.
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Sponsor organisation address |
12F, Hankyu Terminal Bldg., 1-4, Shibata 1-chome, Osaka, Japan,
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Public contact |
Corporate Communications Department, Shionogi & Co., Ltd., shionogiclintrials-admin@shionogi.co.jp
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Scientific contact |
Corporate Communications Department, Shionogi & Co., Ltd., shionogiclintrials-admin@shionogi.co.jp
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-002440-PIP01-18 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
09 Aug 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
25 Mar 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
25 Mar 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective of this study was to evaluate the efficacy of a single oral dose of baloxavir marboxil compared with placebo in the prevention of influenza virus infection in subjects who were
household members of influenza-infected patients
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Protection of trial subjects |
All study subjects were required to read and sign an Informed Consent Form
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
09 Nov 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Japan: 749
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Worldwide total number of subjects |
749
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
6
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Children (2-11 years) |
136
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Adolescents (12-17 years) |
33
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Adults (18-64 years) |
551
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From 65 to 84 years |
21
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85 years and over |
2
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Recruitment
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Recruitment details |
- | |||||||||||||||
Pre-assignment
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Screening details |
752 subjects were randomized in this study but only 749 (374 in the baloxavir marboxil group and 375 in the placebo group) were included in the safety and efficacy analyses. 2 subjects were not dosed and 1 subject was discontinued due to non-compliance. | |||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Baloxavir Marboxil | |||||||||||||||
Arm description |
Participants will receive a single oral dose of baloxavir marboxil on Day 1 (based on body weight) | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
S-033188
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Investigational medicinal product code |
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Other name |
Baloxavir Marboxil
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Pharmaceutical forms |
Granules, Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
S-033188 is available as 20-mg tablets or 2% granules (containing 20 mg of baloxavir marboxil per 1 g of granules). Subjects ≥12 years of age at screening were administered 40 mg if their body weight was < 80 kg or 80 mg if their body weight was ≥ 80 kg. Subjects < 12 years of age at screening were administered 1 mg/kg (weight < 10 kg) or 10 mg (Weight 10 to < 20 kg) or 20 mg (weight 20 to < 40 kg) or 40 mg (Weight ≥ 40 kg)
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Arm title
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Placebo | |||||||||||||||
Arm description |
Participants will receive a single oral dose of matching placebo | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Granules, Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo was available as tablets or granules. Subjects ≥12 years of age at screening were administered 2 placebo tablets if their body weight was < 80 kg or 4 placebo tablets if their body weight was ≥ 80 kg. Subjects < 12 years of age at screening were administered granules (50 mg/kg if weight < 10 kg) or 1 placebo granule packet (Weight 10 to < 20 kg) or 1 placebo tablet (weight 20 to < 40 kg) or 2 placebo tablets (Weight ≥ 40 kg).
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Baseline characteristics reporting groups
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Reporting group title |
Baloxavir Marboxil
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Reporting group description |
Participants will receive a single oral dose of baloxavir marboxil on Day 1 (based on body weight) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants will receive a single oral dose of matching placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Baloxavir Marboxil
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Reporting group description |
Participants will receive a single oral dose of baloxavir marboxil on Day 1 (based on body weight) | ||
Reporting group title |
Placebo
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Reporting group description |
Participants will receive a single oral dose of matching placebo |
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End point title |
Proportion of subjects who are infected with influenza virus (RT-PCR positive), and present with fever and at least one respiratory symptom | ||||||||||||
End point description |
Influenza virus infection was confirmed through Reverse transcription polymerase chain reaction (RT-PCR positive). Fever was defined as subjects having a body temperature (axillary) of ≥37.5°C. Respiratory symptoms included having cough or nasal discharge/nasal congestion with a severity of 2: Moderate or 3: Severe as assessed in the subject diary.
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End point type |
Primary
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End point timeframe |
Day 1 to Day 10
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Statistical analysis title |
Baloxavir versus Placebo | ||||||||||||
Comparison groups |
Placebo v Baloxavir Marboxil
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Number of subjects included in analysis |
749
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
modified Poisson regression approach | ||||||||||||
Parameter type |
Risk ratio (RR) | ||||||||||||
Point estimate |
0.14
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.06 | ||||||||||||
upper limit |
0.3 |
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End point title |
Time from study treatment to the time when fever, at least one respiratory symptom, and influenza virus infection (RT-PCR) were observed | ||||||||||||
End point description |
An influenza infection proportion curve based on the length of time from the study treatment to the first time point when fever, at least one respiratory symptom (cough and/or nasal discharge/nasal congestion), and influenza virus infection were all confirmed was plotted by treatment group, using the Kaplan-Meier method. Restricted mean survival time (RMST) up to Day 10 in each treatment group was estimated by integrating the Kaplan-Meier survival curve. If a subject had no positive test result for influenza virus or has no fever or any respiratory symptom (cough or nasal discharge/nasal congestion) at any time after the study treatment, the subject was handled as a censored case at the last observation time point.
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End point type |
Secondary
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End point timeframe |
Day 1 (baseline) to study end (approximately 15 days)
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Statistical analysis title |
Difference in RMST up to day 10 (day) | ||||||||||||
Comparison groups |
Baloxavir Marboxil v Placebo
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Number of subjects included in analysis |
749
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
RMST | ||||||||||||
Point estimate |
0.8
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.6 | ||||||||||||
upper limit |
1 |
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End point title |
Proportion of subjects who are infected with influenza virus (RT-PCR positive), and present with fever or at least one influenza symptom | ||||||||||||
End point description |
Influenza symptoms could be a respiratory symptom (cough or nasal discharge/nasal congestion) or a systemic symptom (headache, feverishness or chills, muscle or joint pain, fatigue).
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End point type |
Secondary
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End point timeframe |
Day 1 (baseline) to Day 10
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Statistical analysis title |
Baloxavir Marboxil vs. Placebo | ||||||||||||
Comparison groups |
Baloxavir Marboxil v Placebo
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Number of subjects included in analysis |
749
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
modified Poisson regression approach | ||||||||||||
Parameter type |
Risk ratio (RR) | ||||||||||||
Point estimate |
0.24
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.15 | ||||||||||||
upper limit |
0.38 |
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End point title |
Time from study treatment to the time when fever or at least one influenza symptom, and influenza virus infection (RT-PCR) are observed. | ||||||||||||
End point description |
Restricted mean survival time (RMST) up to Day 10 in each treatment group was estimated by integrating the Kaplan-Meier survival curve.
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End point type |
Secondary
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End point timeframe |
Day 1 (baseline) to study end (approximately 15 days)
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Statistical analysis title |
Difference in RMST up to Day 10 | ||||||||||||
Comparison groups |
Baloxavir Marboxil v Placebo
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Number of subjects included in analysis |
749
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
RMST | ||||||||||||
Point estimate |
1.3
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1 | ||||||||||||
upper limit |
1.6 |
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End point title |
Proportion of asymptomatic influenza-infected (RT-PCR positive) subjects | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 1 (baseline) to Day 10
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Statistical analysis title |
Baloxavir Marboxil vs. Placebo | ||||||||||||
Comparison groups |
Baloxavir Marboxil v Placebo
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Number of subjects included in analysis |
749
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.9917 | ||||||||||||
Method |
modified Poisson regression approach | ||||||||||||
Parameter type |
Risk ratio (RR) | ||||||||||||
Point estimate |
1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.61 | ||||||||||||
upper limit |
1.64 |
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End point title |
Proportion of subjects with influenza virus infection (RT-PCR positive) | ||||||||||||
End point description |
The proportion of subjects with influenza virus infection (RT-PCR positive) regardless of symptoms
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End point type |
Secondary
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End point timeframe |
Day 1 (baseline) to Day 10
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Statistical analysis title |
Baloxavir Marboxil vs. Placebo | ||||||||||||
Comparison groups |
Baloxavir Marboxil v Placebo
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Number of subjects included in analysis |
749
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
modified Poisson regression approach | ||||||||||||
Parameter type |
Risk ratio (RR) | ||||||||||||
Point estimate |
0.43
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.32 | ||||||||||||
upper limit |
0.58 |
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End point title |
Proportion of subjects with Adverse Events (AEs) | |||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 1 (baseline) to study end (approximately 15 days)
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No statistical analyses for this end point |
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End point title |
Maximum plasma concentration (Cmax) of S-033447 [1] | ||||||||||||||||
End point description |
I = Influenza-infected subjects with fever and at least one respiratory symptom; and O = The other subjects.
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End point type |
Secondary
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End point timeframe |
Day 1 (baseline) to study end (approximately 15 days)
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Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: S-033447 concentrations were only measured in the Baloxavir Marboxil arm. |
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No statistical analyses for this end point |
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End point title |
Area under the plasma concentration-time curve extrapolated from time zero to infinity (AUC0-inf) of S-033447 [2] | ||||||||||||||||
End point description |
I = Influenza-infected subjects with fever and at least one respiratory symptom; and O = The other subjects.
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End point type |
Secondary
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End point timeframe |
Day 1 (baseline) to study end (approximately 15 days)
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Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: S-033447 concentrations were only measured in the Baloxavir Marboxil arm. |
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No statistical analyses for this end point |
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End point title |
Plasma concentration 24 hours post-dose (C24) of S-033447 [3] | ||||||||||||||||
End point description |
I = Influenza-infected subjects with fever and at least one respiratory symptom; and O = The other subjects.
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End point type |
Secondary
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End point timeframe |
Day 1 (baseline) to 24 hours post-dose
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Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: S-033447 concentrations were only measured in the Baloxavir Marboxil arm. |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Day 1 (baseline) to study end (approximately 15 days)
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||
Dictionary version |
21.0
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Reporting groups
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Reporting group title |
Baloxavir Marboxil
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Reporting group description |
Participants will receive a single oral dose of baloxavir marboxil on Day 1 (based on body weight) | ||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants will receive a single oral dose of matching placebo | ||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |