Clinical Trial Results:
A Phase 3, Randomized, Double Blind, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Favipiravir in Adult Subjects with Uncomplicated Influenza
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Summary
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EudraCT number |
2013-002149-13 |
Trial protocol |
BE HU BG NL ES SE |
Global end of trial date |
16 Mar 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
03 Jun 2016
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First version publication date |
03 Jun 2016
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Other versions |
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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 |
T705aUS316
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
U1111-1147-8470 | ||
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Sponsors
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Sponsor organisation name |
MDVI, LLC
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Sponsor organisation address |
One Post Office Square, Boston , United States, 02109
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Public contact |
Robert Morgan, MDVI, LLC, +1 617-398-5978, rmorgan@medivector.com
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Scientific contact |
Carol R. Epstein, MD, MDVI, LLC, +1 617-398-5911, cepstein@medivector.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Sep 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
16 Mar 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Mar 2015
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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 primary objective of this study was to evaluate the clinical efficacy of favipiravir compared with placebo in treating adult subjects with confirmed uncomplicated influenza.
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Protection of trial subjects |
This study was conducted in accordance with GCP, as described in International Conference on Harmonisation (ICH) Guideline E6, Good Clinical Practice, Consolidated Guidance (April 1996). The ICH GCP guideline is consistent with the World Medical Assembly Declaration of Helsinki.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
21 Jan 2014
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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 |
Poland: 43
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Country: Number of subjects enrolled |
Netherlands: 5
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Country: Number of subjects enrolled |
Spain: 22
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Country: Number of subjects enrolled |
Sweden: 3
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Country: Number of subjects enrolled |
Belgium: 11
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Country: Number of subjects enrolled |
Bulgaria: 47
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Country: Number of subjects enrolled |
Hungary: 2
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Country: Number of subjects enrolled |
Australia: 35
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Country: Number of subjects enrolled |
Russian Federation: 10
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Country: Number of subjects enrolled |
Turkey: 6
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Country: Number of subjects enrolled |
Ukraine: 9
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Country: Number of subjects enrolled |
United States: 527
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Country: Number of subjects enrolled |
New Zealand: 14
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Country: Number of subjects enrolled |
South Africa: 126
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Worldwide total number of subjects |
860
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EEA total number of subjects |
133
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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) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
799
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From 65 to 84 years |
61
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects were recruited from local sites and their environs (from database, First Patient First Visit 21 January 2014, Last Patient Last Visit 16 Mart 2015). | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Subjects were screened and randomized on the same day. ICF, pregnancy test, Inclusion Criteria/Exclusion Criteria, RAT test, demographics and medical history, height/weight measurements, physical examination, vital signs, body temperature (oral), assessment of influenza symptoms, 12-lead electrocardiogram (ECG), Randomization. | ||||||||||||||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
860 | ||||||||||||||||||||||||||||||
Number of subjects completed |
855 | ||||||||||||||||||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Randomized but not dosed: 5 | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Treatment period (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, Monitor, Data analyst | ||||||||||||||||||||||||||||||
Blinding implementation details |
The study remained blinded with regard to treatment assignments until all subjects left the study, all queries had been resolved, a signed final Statistical Analysis Plan was available and the database had been locked. The determination of inclusion and exclusion of subjects in the various analysis populations was finalized prior to database lock and unblinding.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Favipiravir | ||||||||||||||||||||||||||||||
Arm description |
Nine tablets (1800 mg) BID for a total daily dose of 3600 mg on Day 1, followed by 4 tablets (800 mg) BID for a total daily dose of 1600 mg on Days 2 to 5. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Favipiravir
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Nine tablets (1800 mg) BID for a total daily dose of 3600 mg on Day 1, followed by 4 tablets (800 mg) BID for a total daily dose of 1600 mg on Days 2 to 5.
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Arm title
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Placebo | ||||||||||||||||||||||||||||||
Arm description |
Nine tablets (to mimic 1800 mg) BID on Day 1, followed by 4 tablets (to mimic 800 mg) BID on Days 2 to 5. | ||||||||||||||||||||||||||||||
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 |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Nine tablets (to mimic 1800 mg) BID on Day 1, followed by 4 tablets (to mimic 800 mg) BID on Days 2 to 5.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 5 subjects were randomized but not dosed. |
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Baseline characteristics reporting groups
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Reporting group title |
Favipiravir
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Reporting group description |
Nine tablets (1800 mg) BID for a total daily dose of 3600 mg on Day 1, followed by 4 tablets (800 mg) BID for a total daily dose of 1600 mg on Days 2 to 5. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Nine tablets (to mimic 1800 mg) BID on Day 1, followed by 4 tablets (to mimic 800 mg) BID on Days 2 to 5. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Primary Efficacy Analysis
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Subject analysis set type |
Intention-to-treat | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The ITT (Intent to Treat) population included all subjects who were randomized and received any amount of study drug. These subjects were analyzed as randomized.
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Subject analysis set title |
Primary Efficacy Analysis
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Subject analysis set type |
Modified intention-to-treat | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The ITTI (Intent to Treat-Infected) population, a subset of the ITT population, was the primary efficacy population and was also used for all analyses of antiviral efficacy. It included all randomized subjects who had received any amount of study drug and were subsequently confirmed as having influenza by RT- PCR from samples collected prior to first dose.
Subjects were analyzed according to the treatment they were randomized to receive.
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Subject analysis set title |
Primary Efficacy Analysis
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Subject analysis set type |
Sub-group analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The uninfected population was a subset of the ITT population that included subjects who did not have a positive RT- PCR on Day 1 (ITT minus ITTI).
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Subject analysis set title |
Safety Analysis
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Subject analysis set type |
Safety analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The safety population included all subjects who received any amount of study drug. In the case of any discrepancy (ie, treatment misallocation) subjects were analyzed according to the treatment actually received, not as randomized.
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End points reporting groups
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Reporting group title |
Favipiravir
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Reporting group description |
Nine tablets (1800 mg) BID for a total daily dose of 3600 mg on Day 1, followed by 4 tablets (800 mg) BID for a total daily dose of 1600 mg on Days 2 to 5. | ||
Reporting group title |
Placebo
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Reporting group description |
Nine tablets (to mimic 1800 mg) BID on Day 1, followed by 4 tablets (to mimic 800 mg) BID on Days 2 to 5. | ||
Subject analysis set title |
Primary Efficacy Analysis
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The ITT (Intent to Treat) population included all subjects who were randomized and received any amount of study drug. These subjects were analyzed as randomized.
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Subject analysis set title |
Primary Efficacy Analysis
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
The ITTI (Intent to Treat-Infected) population, a subset of the ITT population, was the primary efficacy population and was also used for all analyses of antiviral efficacy. It included all randomized subjects who had received any amount of study drug and were subsequently confirmed as having influenza by RT- PCR from samples collected prior to first dose.
Subjects were analyzed according to the treatment they were randomized to receive.
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Subject analysis set title |
Primary Efficacy Analysis
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The uninfected population was a subset of the ITT population that included subjects who did not have a positive RT- PCR on Day 1 (ITT minus ITTI).
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Subject analysis set title |
Safety Analysis
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The safety population included all subjects who received any amount of study drug. In the case of any discrepancy (ie, treatment misallocation) subjects were analyzed according to the treatment actually received, not as randomized.
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End point title |
Time to alleviation of symptoms and resolution of fever (“alleviation”). | |||||||||||||||
End point description |
The time to alleviation of symptoms and resolution of fever (“alleviation”), defined as the first time point when all of the six influenza symptoms (body aches and pains, cough, fatigue, headache, nasal congestion, and sore throat) were either absent or mild and fever had resolved, with both maintained for at least 21.5 hours.
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End point type |
Primary
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End point timeframe |
Day 1 subjects began study treatment within 48 hours after onset of influenza symptoms.Subjects returned to the clinic on Days 2 to 5 for assessments of influenza.Subjects returned to the clinic for a follow-up visit on Day 15 and a final visit on Day 22.
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Statistical analysis title |
Primary efficacy endpoint | |||||||||||||||
Statistical analysis description |
Statistical testing was performed using Peto-Peto Prentice test, comparing placebo vs favipiravir. Median time to alleviation was the duration between first dose to the first alleviation of all symptoms and resolution of fever. The median time to alleviation was calculated using Kaplan Meier method, which assess the time that 50% of the subjects reaching alleviation.
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Comparison groups |
Favipiravir v Placebo
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Number of subjects included in analysis |
623
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
≤ 0.05 | |||||||||||||||
Method |
Peto-Peto Prentice test | |||||||||||||||
Parameter type |
Median difference (final values) | |||||||||||||||
Confidence interval |
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95% | |||||||||||||||
sides |
2-sided
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lower limit |
- | |||||||||||||||
upper limit |
- | |||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
The Investigator was required to notify the Sponsor of the SAE within 24 hours, via the electronic data capture (EDC) system or, in the event of EDC failure, by using the email or fax number printed on the SAE form.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15
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Reporting groups
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Reporting group title |
Favipiravir
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Reporting group description |
Nine tablets (1800 mg) BID for a total daily dose of 3600 mg on Day 1, followed by 4 tablets (800 mg) BID for a total daily dose of 1600 mg on Days 2 to 5. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Nine tablets (to mimic 1800 mg) BID on Day 1, followed by 4 tablets (to mimic 800 mg) BID on Days 2 to 5. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? Yes | |||
Date |
Amendment |
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24 May 2013 |
The main changes listed below were made to the original protocol dated 15 May 2013. Treatment regimen was changed from TID to BID dosing, frequency of subjects’ assessment in the subject diary of their ability to return to normal activity was changed from daily to three times daily. Text was added to indicate that subjects were required to receive the first dose of study medication within 48 hours of the initial onset of influenza symptoms. No subjects were ever enrolled under the initial protocol dated 15 May 2013. |
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12 Feb 2014 |
New text was added to indicate that subjects’ age range could be determined in accordance with national standards in each country, new text was added to indicate that if the subject was unable or unwilling to come to the study site, study site personnel could conduct the Days 2, 3 and/or 4 visits at the subjects home, previous text advising that subjects not take more than two doses in a 24 hour period was deleted and new text was added to indicate that optimal dosing interval is 12 hours apart, addition of instruction that subjects should minimize exposure to sunlight or artificial ultraviolet light during study drug treatment, updates to information regarding the reporting of AEs, including relationship to study drug, pregnancy, and in utero drug exposure. |
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12 Jan 2015 |
Addition of US sites and revised the total planned number of subjects to up to 860 to provide for greater precision in the estimations of treatment effects and to increase the safety database to better meet regulatory guidelines. |
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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 | |||
