Clinical Trial Results:
The Effect of Live Attenuated Influenza Vaccine (LAIV) on Experimental Human Pneumococcal Colonisation (EHPC) Study
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Summary
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EudraCT number |
2014-004634-26 |
Trial protocol |
GB |
Global end of trial date |
29 Sep 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
18 May 2019
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First version publication date |
18 May 2019
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Other versions |
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Summary report(s) |
Effect of Live Attenuated Influenza Vaccine on Pneumococcal Carriage Effect of Live Attenuated Influenza Vaccine on Pneumococcal Carriage Biovax |
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 |
4896
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Additional study identifiers
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ISRCTN number |
ISRCTN16993271 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Liverpool School of Tropical Medicine/Royal Liverpool Hospital
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Sponsor organisation address |
Daulby Street, Liverpool, United Kingdom, L7 8XP
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Public contact |
Dr Helen Hill, Liverpool School of Tropical Medicine, +44 01517029338, helen.hill@lstmed.ac.uk
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Scientific contact |
Professor Daniela Ferreira (Scientific)
Dr Jamie Rylance (Clinical), Liverpool School of Tropical Medicine, +44 0151702 9338, daniela.ferriera@lstmed.ac.uk
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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 |
29 Sep 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
29 Sep 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
29 Sep 2017
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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 |
To define the effect of Live Attenuated Influenza Vaccine (LAIV) on pneumococcal colonisation using the Experimental Human Pneumococcal Carriage (EHPC) Model in order to assess the potential effects of mass influenza vaccination including colonisation acquisition, density and duration.
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Protection of trial subjects |
An Independent Data Safety Monitoring Committee provide oversight to the trial monitoring safety reports consistent with requirements of pharmacovigilance reporting requirements by the MHRA and NHS National Research ethics Service.
For the duration of the trial participants report adverse events and Serious Adverse Events consistent with both the MHRA and National Research Ethics Service pharmacovigilance reporting requirements.Participants follow up was consistent with the Experimental Human Pneumococcal Carriage safety guidelines. A respiratory clinician is available day and night. Post-inoculation participants contact the team to reported symptoms and their temperature daily >7 days. Participants are assessed by a clinician in the event of symptoms. A safety information sheet is provided to participants.
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Background therapy |
This study design includes: Participants being inoculated nasally with Streptococcus Pneumoniae then comparing being randomised to either the intervention Live Attenuated Influenza Spray plus IM placebo or control Quadrivalent Inactivated Influenza Vaccine (intramuscular) plus nasal placebo to determine carriage. Study 1 Immunise first (antecedent) Study: vaccinate then inoculate Study 1 Colonise first (concurrent ) Study: inoculate then vaccinate To blind the participants the control group are administered an intramuscular quadrivalent inactivated influenza vaccine (QIV) with a saline placebo to blind the route of administration | ||
Evidence for comparator |
There are 2 types of influenza vaccines currently available, a quadrivalent live attenuated influenza vaccine (LAIV) which is administered as a nasal spray and a quadrivalent inactivated influenza vaccine (QIV) administered as an intramuscular injection. Quadrivalent LAIV and QIV contain four influenza strains, 2 influenza A (H1N1 and H3N2) and 2 influenza B. Both are licensed for the prevention of influenza in the UK. Although LAIV has been proven to be safe and effective in numerous trials, no trial has assessed its potential impact on other nasopharyngeal pathogens. | ||
Actual start date of recruitment |
26 Aug 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
United Kingdom: 335
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Worldwide total number of subjects |
335
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EEA total number of subjects |
335
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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) |
335
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Healthy volunteers aged 18 to 50 years recruited in a single centre within the National Health Service in Liverpool, UK over the period of 18 months . | |||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Screened day -7 348 screened study 1 n=142 study 2 n= 206 (excluded unable to attend 9 appointments, GP health history not available/ineligible (e.g allergy to antibiotics/concomitant medication) 335 randomised (excludes 13 screen fails including acute infection, abnormal vital signs or FBC) 331 vaccinated 323 vaccinated and inoculated | |||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Study 1 and 2 (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 |
Investigator, Assessor, Subject | |||||||||||||||||||||||||||
Blinding implementation details |
The clinical research team, participants and laboratory scientists were blinded. An independent blinding team administered the vaccine. During vaccination participants wore a blindfold and received both an intramuscular and a nasal dose pairing the vaccine with a placebo (for example the LAIV vaccine (nasal) with an intramuscular placebo or the QIV vaccine (intramuscular with a nasal spray placebo).
Blinding the participant aimed to remove bias when reporting symptoms.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Study 1 and 2 Intervention: | |||||||||||||||||||||||||||
Arm description |
Live Attenuated Influenza Vaccine (LAIV) given as a nasal spray with a placebo intramuscular injection of saline. After 3 days participants were inoculated nasally Streptococcus pneumoniae 6B wild type | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Live Attenuated Influenza Vaccine
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Investigational medicinal product code |
EU/1/13/887/004
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Other name |
Fluenz or Fluarix
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Pharmaceutical forms |
Nasal spray, suspension
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Routes of administration |
Intranasal use , Nasal use
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Dosage and administration details |
Dose 0.2ml (0.1ml per nostril)
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Arm title
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Control: | |||||||||||||||||||||||||||
Arm description |
Inoculate with Streptococcus Pneumoniae then after 3 days immunise with Quadrivalent Inactivated Influenza Vaccination administered by intramuscular injection Fluarix Tetra, GlaxoSmithKline, UK paired with a placebo nasal spray using saline administered via a Mad Nasal LMA Nasal Atomizer | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
Quadrivalent Inactivated Influenza Vaccination Fluarix Tetra (IM)
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Investigational medicinal product code |
PL 10592/0302
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Other name |
Fluarix Tetra, GlaxoSmithKline, UK
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
0.5 ml intramuscular injection paired with a saline nasal spray
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Baseline characteristics reporting groups
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Reporting group title |
Study 1 and 2
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Reporting group description |
These data combine: Study 1 : intervention and control Study 2 : intervention and control | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Study 1 Intervention
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Healthy volunteers are randomised to be vaccinated with the Live Attenuated Influenza Vaccine (nasal spray) and a intramuscular injection of a saline placebo followed by nasal inoculation aiming to collonise with Streptococcus Pneumoniae.
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Subject analysis set title |
Study 1 Control
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Healthy volunteers are randomised to be vaccinated with the Quadrivalent Inactivated Influenza Vaccine FLuarix and a nasal spray saline placebo followed by nasal inoculation aiming to collonise with Streptococcus Pneumoniae.
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Subject analysis set title |
Study 2 Intervention
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Healthy volunteers are inoculated nasally aiming to collonise with Streptococcus Pneumoniae then after three days randomised to be vaccinated with the Live Attenuated Influenza Vaccine (nasal spray) and a intramuscular injection of a saline placebo
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Subject analysis set title |
Study 2 Control
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Healthy volunteers are inoculated nasally aiming to achieve carriage of Streptococcus Pneumoniae then after three days vaccinated with the Quadrivalent Inactivated Influenza Vaccine Fluarix Tetra (IM) plus a placebo nasal saline spray.
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End points reporting groups
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Reporting group title |
Study 1 and 2 Intervention:
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Reporting group description |
Live Attenuated Influenza Vaccine (LAIV) given as a nasal spray with a placebo intramuscular injection of saline. After 3 days participants were inoculated nasally Streptococcus pneumoniae 6B wild type | ||
Reporting group title |
Control:
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Reporting group description |
Inoculate with Streptococcus Pneumoniae then after 3 days immunise with Quadrivalent Inactivated Influenza Vaccination administered by intramuscular injection Fluarix Tetra, GlaxoSmithKline, UK paired with a placebo nasal spray using saline administered via a Mad Nasal LMA Nasal Atomizer | ||
Subject analysis set title |
Study 1 Intervention
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Healthy volunteers are randomised to be vaccinated with the Live Attenuated Influenza Vaccine (nasal spray) and a intramuscular injection of a saline placebo followed by nasal inoculation aiming to collonise with Streptococcus Pneumoniae.
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Subject analysis set title |
Study 1 Control
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Healthy volunteers are randomised to be vaccinated with the Quadrivalent Inactivated Influenza Vaccine FLuarix and a nasal spray saline placebo followed by nasal inoculation aiming to collonise with Streptococcus Pneumoniae.
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Subject analysis set title |
Study 2 Intervention
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Healthy volunteers are inoculated nasally aiming to collonise with Streptococcus Pneumoniae then after three days randomised to be vaccinated with the Live Attenuated Influenza Vaccine (nasal spray) and a intramuscular injection of a saline placebo
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Subject analysis set title |
Study 2 Control
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Healthy volunteers are inoculated nasally aiming to achieve carriage of Streptococcus Pneumoniae then after three days vaccinated with the Quadrivalent Inactivated Influenza Vaccine Fluarix Tetra (IM) plus a placebo nasal saline spray.
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End point title |
Study 1 Immunise First (antecedent) | ||||||||||||
End point description |
Study 1 Immunise First
Primary outcome: Study 1 - Primary outcome: detection of pneumococcal bacteria in the nasal wash sample at any time point after inoculation by classical microbiology.
Primary end point is the occurrence of pneumococcal colonisation determined by the presence of pneumococcus in NW at each time point post inoculation (days 2, 7, 9, 14, 22 and 29
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End point type |
Primary
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End point timeframe |
Presence of carriage of Streptococcus Pneumoniae at any time point
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Statistical analysis title |
Study 1 Immunise First Primary Outcome | ||||||||||||
Comparison groups |
Study 1 Control v Study 1 Intervention
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Number of subjects included in analysis |
117
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||
P-value |
= 0.46 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.32
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.63 | ||||||||||||
upper limit |
2.77 | ||||||||||||
Variability estimate |
Standard deviation
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| Notes [1] - 202 participants consented, of which 142 were screened, 137 were vaccinated, 130 were inoculated, and 117 participants entered the modified ITT analysis (n=55 LAIV, n=62 control) Comparison of the primary endpoint showed similar overall carriage rates in LAIV participants and controls (25/55 [45.5%] vs 24/62 [38.7%], OR=1.32, p=0.46). |
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End point title |
Study 2 Colonise First (concurrent) | ||||||||||||
End point description |
Primary outcome:
Primary end point was AUC bacterial density to day 14 by conventional microbiology.
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End point type |
Primary
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End point timeframe |
Primary outcome of Streptococcus Pneumoniae at any time point following inoculation until day 14
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Statistical analysis title |
Study 2 Primary Outcome | ||||||||||||
Statistical analysis description |
316 participants consented, 206 were screened, 198 were inoculated and 194 vaccinated. Data from 163 participants entered the modified ITT.
There was no significant difference in the primary endpoint of AUC carriage density by conventional microbiology to day 14, (mean±SD 20.93±14.07 and 26.10±14.41 in LAIV and controls respectively, p=0.11)
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Comparison groups |
Study 2 Intervention v Study 2 Control
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Number of subjects included in analysis |
163
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.11 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||
Point estimate |
5.17
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.08 | ||||||||||||
upper limit |
11.41 | ||||||||||||
Variability estimate |
Standard deviation
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events were recorded until 30 days after inoculation per participant for the duration of the study
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Adverse event reporting additional description |
Pharmacovigilance reporting was consistent with MHRA and National Research Ethics Service. There were no Serious Adverse events reported. Participants with respiratory or ENT symptoms were assessed by the study clinician and no adverse events were assessed as related. Symptom data was assessed at each study visit (average 8 visits)
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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 |
19
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Reporting groups
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Reporting group title |
Live Attenuated Influenza Vaccine and placebo
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Reporting group description |
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Reporting group title |
Quadrivalent inactivated Influenza Vaccination and placebo
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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30 Apr 2014 |
Amendment 1
Change of Chief Investigator to Professor Neil French.
Sponsor- addition of Co-sponsor with NHS Site.
Samples: additional blood samples
Exclusion criterior clarified. |
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30 Apr 2015 |
Amendment 2
Trial Oversight ; formalisation of roles for DSMG, TSC and TMG.
Participants samples: minor change to bloods, and nasal samples
Exlcusion criterior clarified. |
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16 Dec 2015 |
Amendment 3:
IMP: MHRA and Public Health England confirmed FLumist may be administered nasally due to Fluenz shoratge.
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13 Sep 2016 |
Amendment 4
Statistical Analysis plan revised based on advice by the Trial Steering Group for the concurrent study ( inoculate then vaccinate) from % carriage rates to area under the curve with an increase in sample size to 156.
Summary of Poroduct Characteristics: updated Fluarix Tetra and Fluenz.
Minor changes to participant information, symptom log and sampling. |
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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 | |||
