Clinical Trial Results:
FULL TITLE: Pneumococcal Conjugate Vaccine (PCV-13) and Experimental Human Pneumococcal Carriage Study (EHPC) Study.
KEY WORDS: mucosa, innate, cellular, humoral, Streptococcus pneumoniae, pneumococcus, carriage, colonisation, human, lung, antibody, vaccine, T-cells, genome sequencing, conjugate vaccine, protection.
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Summary
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EudraCT number |
2012-005141-20 |
Trial protocol |
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Global end of trial date |
07 Nov 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
16 May 2019
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First version publication date |
16 May 2019
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Other versions |
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Summary report(s) |
First Human Challenge Testing of a Pneumococcal Vaccine: Double Blind Randomised Control Trial |
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 |
4431
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Royal Liverpool and Broadgreen University Hospital
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Sponsor organisation address |
Prescott Street, Liverpool, United Kingdom, L7 8XP
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Public contact |
Heather Rogers, Royal Liverpool and Broadgreen University Hospital Trust, +44 1517063320, rgt@rlbuht.nhs.uk
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Scientific contact |
Heather Rogers, Royal Liverpool and Broadgreen University Hospital Trust, +44 1517063320, rgt@rlbuht.nhs.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 |
07 Nov 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
07 Nov 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Nov 2014
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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 study aim is to determine whether PCV is protective against pneumococcal carriage in healthy adult volunteers.
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Protection of trial subjects |
All participants were given emergency antbiotics (amoxicillin 500mg TDS for 3/7 supply) to be taken if instructed by the research team/ if unwell and unable to contact the research team/ at the end of the study if they were positive for colonization. They were also given a thermometer and an emergency contact card with 24/7 access to the research team.
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Background therapy |
All participants were nasally inoculated with 80,000CFU/0.1ml of SPN6B pneumococcal bacteria in each nostril. All participants underwent research samples including blood, nasal wash and saliva smaples during the screen and follow up period as per protocol. | ||
Evidence for comparator |
The participants were randomly allocated to receive either Pneumococcal Conjugate Vaccine (PCV13) OR Hepatitis A vaccine (Avaxim: Control). The control vaccine was chosen as it contains a similar adjuvant compound and therefore it should cause similar localised reactions however it is not known to affect nasal immunity. The control vaccine is also beneficial to the participant and all participants were offered the full course of Hep A at the end of the study. | ||
Actual start date of recruitment |
01 Mar 2013
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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: 99
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Worldwide total number of subjects |
99
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EEA total number of subjects |
99
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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) |
99
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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 |
100 healthy volunteers were recruited into the study over the 9 month period. Consort statement available in publication online. T | |||||||||||||||||||||
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Pre-assignment
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Screening details |
All participants were screened against the inclusion and exclusion criteria. During the screening visit, all participants were given a clinical examination: listen to their heart and lungs, medical history taken (by a research Dr or a delegated person), vital signs monitored, full blood count was taken to ensure that they have an adequate immunity. | |||||||||||||||||||||
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Period 1
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Period 1 title |
Randomisation and vaccination (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, Data analyst, Assessor | |||||||||||||||||||||
Blinding implementation details |
Separate unblinding team of nurses administered the vaccine to the participant using sealed envelopes. The unblided team had no further involvement in the trial. All research staff including clinical staff and lab staff were blinded to the randomisation. Unblinding only occured at the end of the study, last subject, last visit once all of the data had been locked down.
Participants were later unblinded by sending a vaccine letter explaining theoir allocation, a copy was also sent to their GP.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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PCV Intervention | |||||||||||||||||||||
Arm description |
Randomised to receive Pneumococcal Conjugate Vaccine (PCV13) | |||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||
Investigational medicinal product name |
Prevenar
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Investigational medicinal product code |
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Other name |
Pneumococcal Conjugate Vaccine PCV13
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
PCV13 one dose given by intramuscular injection by a member of the unblinded nursing team
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Arm title
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Control: Hepatitis A Vaccine | |||||||||||||||||||||
Arm description |
Hepatitis A vaccine: Avaxim | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Avaxim
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Investigational medicinal product code |
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Other name |
Hepatitis A Vaccine
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Avaxim one dose given by intramuscular injection by a member of the unblinded nursing team
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Baseline characteristics reporting groups
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Reporting group title |
PCV Intervention
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Reporting group description |
Randomised to receive Pneumococcal Conjugate Vaccine (PCV13) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control: Hepatitis A Vaccine
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Reporting group description |
Hepatitis A vaccine: Avaxim | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
PCV Intervention
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Reporting group description |
Randomised to receive Pneumococcal Conjugate Vaccine (PCV13) | ||
Reporting group title |
Control: Hepatitis A Vaccine
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Reporting group description |
Hepatitis A vaccine: Avaxim | ||
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End point title |
Pneumococcal Colonization at any time point | |||||||||||||||
End point description |
Pneumococcal colonization is determined by the presence of SPN6B pneumococcus in the nasal wash using classical microbiological culture at any time point post nasal inoculation (Day 2, Day 7, Day 14 and Day 21)
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End point type |
Primary
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End point timeframe |
Colonization assessed at Day 2, Day 7, Day 14 and Day 21 post nasal inoculation. Primary endpoint is colonization at any of these time points post inoculation
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Attachments |
Publication with tables |
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| Notes [1] - One subject withdrew due to anxiety following the randomisation and vaccination [2] - One subject removed due to a low white cell count. One subject withdrew consent post vaccination an |
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Statistical analysis title |
Generalized linear model | |||||||||||||||
Statistical analysis description |
The primary endpoint was analyzed using a generalized linear model with treatment as a single predictor, generating risk ratios and odds ratios together with their 95% confidence intervals (CIs) of being colonized with pneumococcus between the PCV and control groups.
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Comparison groups |
PCV Intervention v Control: Hepatitis A Vaccine
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | |||||||||||||||
P-value |
= 0.0002 [4] | |||||||||||||||
Method |
Generalized linear model. | |||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||
Confidence interval |
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| Notes [3] - Generalized linear model. All statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, NC) and Stata 13 (StataCorp, College Station, TX). All analyses performed by Prof Duolao Wang [4] - Pneumococcal colonization at any time point between PCV and Control group |
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Adverse events information
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Timeframe for reporting adverse events |
Any adverse events would be reported for each participant during the study participation.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||
Dictionary version |
10.0
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Reporting groups
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Reporting group title |
PCV Intervention
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Reporting group description |
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Reporting group title |
Avaxim (Control)
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Reporting group description |
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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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03 Jul 2013 |
Expand unblinded team to include RLUH staff. Participants are offered the complete Hep A course at the end of the study, this is to be arranged between the volunteer and the Well Travelled Clinic.
Addition of throat swab at each visit.
Add comparison of traditional culture methods with qPCR methods to detect bacteria.
Addition of GP questionnaire. |
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18 Dec 2013 |
Take extra blood samples at certain visits.
Prolong the time between completing the challenge study and taking part in the bronchoscopy from 2 weeks to no end date.
Addition of paired blood sample on the day of the bronchoscopy.
FBC full blood count to be taken at pre-vaccine visit AND pre-inoculation visit.
Remove saliva samples throughout.
Increase overall sample size to allow for higher dropout.
Remove the interim analysis after 50 participants to remain blinded until the end of the study.
Addition of a GP vaccination letter to inform the GP of the allocation at the end of the study. |
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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 | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/26114410 |
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