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The Effect of Live Attenuated Inactivated Influenza Vaccine on Experimental Human Pneumococcal Carriage Study (LAIV/EHPC)

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ClinicalTrials.gov Identifier: NCT03502291
Recruitment Status : Completed
First Posted : April 18, 2018
Last Update Posted : April 18, 2018
Sponsor:
Collaborators:
Sponsor GmbH
Liverpool School of Tropical Medicine
Information provided by (Responsible Party):
Royal Liverpool and Broadgreen University Hospitals NHS Trust

Brief Summary:

The investigators are interested in examining the effect of the Live Attenuated Influenza (flu) Vaccine (LAIV) upon nasal carriage of bacteria called Streptococcus pneumoniae (also known as pneumococcus). The nasal spray is a live attenuated vaccine which means that it has weakened virus that does not cause disease. This vaccine is licenced in the United Kingdom for children and adolescents from 2 to 18 years of age.

Pneumococcus can commonly be found harmlessly inhabiting the nose where it does not cause any problem (pneumococcal colonisation). About 10% of adults carry pneumococcus at any one time, and almost all adults experience an episode of carriage at least once per year. Carriage acts as a natural vaccine, boosting immunity against pneumococcal infection in adults and children.

During influenza there is an increase in the burden of pneumococcal pneumonia. We have studied the effects of pneumococcus for many years and have developed a programme in which we can nasally inoculate healthy participants with a dose of pneumococcus and achieve a reproducible carriage rate. The investigators would now like to use this model to investigate the effects of the nasal influenza vaccine upon pneumococcal carriage and to better understand how influenza infections lead to increased susceptibility to pneumonia.

Pneumococcal disease in young adults is rare - less than 10 cases per 100,000 people per year. When pneumococcus does cause problems, usually in young children or elderly people, it can be very serious as it is responsible for diseases such as pneumonia, sepsis and meningitis, which kill millions of children around the world each year.


Condition or disease Intervention/treatment Phase
Pneumonia Influenza, Human Biological: Study one: LAIV + Inoculation Biological: Study one: Placebo + Inoculation Biological: Study two: Inoculation + LAIV Biological: Study two: Inoculation + placebo Phase 4

Detailed Description:

Secondary bacterial infections such as pneumococcal pneumonia are a leading cause of death during influenza endemics. Individuals recently infected with influenza become more susceptible to pneumonia, an effect associated with increased density of pneumococcal carriage in the nose and uncontrolled inflammatory immunological responses. The interaction of influenza virus and pneumococcus has been known and well documented. Recent works have shown that the Live Attenuated Influenza Vaccine (LAIV) enhances pneumococcal carriage in murine models. These results highlighted the potential effect of mass immunization of children with LAIV on pneumococcal carriage. Increased carriage could lead to increased pneumococcal disease in LAIV-vaccinated individuals as well as increased bacterial transmission within the population. LAIV has been licensed for use in children since 2011 in Europe, and has been increasingly administered in children and adults in the USA. There is an urgent need for a clinical trial that will determine the effect of LAIV on pneumococcal carriage dynamics.

The investigators have developed a safe and reproducible experimental human pneumococcal carriage (EHPC) model. The investigators will use EHPC to define the effect of antecedent and concurrent LAIV on pneumococcal carriage acquisition, density and duration. The investigators will perform two double - blinded Randomised Controlled Trials (RCT) to compare LAIV with Quadrivalent Inactivated Influenza Vaccine (QIV). The investigators will compare clinical symptoms, pneumococcal carriage density and duration associated with both vaccines administered antecedent to or concurrently with EHPC inoculation. Changes in the nasopharyngeal microbiome, inflammatory responses in the nasal mucosal and lung cellular immunity associated with influenza virus and pneumococcus interaction will be investigated. This project may provide some reassurance regarding the impact of mass immunization with LAIV on carriage or, if carriage is increased, will provide knowledge of how a natural carriage episode might develop into pneumonia in susceptible subjects during pandemic influenza.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 324 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: DBRCT performed as two studies over two flu seasons. 2 arms to each study.
Masking: Double (Participant, Investigator)
Masking Description: Physical blind folds worn by participant. Unblinded research nurses to deliver the vaccines
Primary Purpose: Health Services Research
Official Title: The Effect of Live Attenuated Inactivated Influenza Vaccine on Experimental Human Pneumococcal Carriage Study
Study Start Date : August 2015
Actual Primary Completion Date : May 2017
Actual Study Completion Date : May 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Study One: LAIV + Inoculation
LAIV Nasal Spray: Inoculation (FLUMIST or FLUENZ) plus intramuscular placebo then inoculation with pneumococci bacteria
Biological: Study one: LAIV + Inoculation
Pneumococci bacteria nasal inoculation following vaccination with LAIV and intramuscular placebo
Other Name: FLUMIST or FLUENZ AstraZeneca

Placebo Comparator: Study One: Placebo + inoculation
Quadrivalent Inactivated Influenza Vaccine Intramuscular (Fluarix Tetra) plus nasal placebo then inoculation with pneumococci bacterial
Biological: Study one: Placebo + Inoculation
Pneumococci bacteria nasal inoculation following vaccination QIV with nasal placebo spray
Other Name: Fluarix Tetra GlaxoSmithKline

Active Comparator: Study Two: Inoculation + LAIV
Inoculation with pneumococci bacteria then Live attenuated Influenza Vaccine Nasal Spray (FLUMIST or FLUENZ) plus intramuscular placebo
Biological: Study two: Inoculation + LAIV
Pneumococci bacteria nasal inoculation prior to vaccination with LAIV and intramuscular placebo
Other Name: FLUMIST or FLUENZ AstraZeneca

Placebo Comparator: Study Two: Inoculation + placebo
Inoculation with pneumococci bacteria then Quadrivalent Inactivated Influenza Vaccine Intramuscular (Fluarix Tetra) plus nasal placebo
Biological: Study two: Inoculation + placebo
Pneumococci bacteria nasal inoculation prior to vaccination QIV with nasal placebo
Other Name: Fluarix Tetra GlaxoSmithKline




Primary Outcome Measures :
  1. Detection of pneumococcal bacteria in the nasal wash sample [ Time Frame: within 6 weeks of inoculation per patient ]
    Primary outcome: detection of pneumococcal bacteria in the nasal wash sample at any time point after inoculation by classical microbiology. 130 participants will complete the study (65 in each arm) to achieve 80% power to detect 50% increase in colonisation rates induced by antecedent LAIV compared to control



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • have capacity to give informed consent
  • aged 18-50 yrs - ages chosen to minimise the risk of pneumococcal infection
  • speak fluent English- to ensure a comprehensive understanding of the research project and their proposed involvement, in order to minimise any communication issues to maximise participant safety.

Exclusion Criteria:

  • currently involved in another study unless observational or in follow-up phase (non-interventional)
  • received any influenza vaccine in the last 2 years

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03502291


Locations
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United Kingdom
Royal Liverpool Hospital
Liverpool, Merseyside, United Kingdom, L7 8XP
Sponsors and Collaborators
Royal Liverpool and Broadgreen University Hospitals NHS Trust
Sponsor GmbH
Liverpool School of Tropical Medicine
Investigators
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Principal Investigator: Jamie Rylance Liverpool School of Tropical Medicine

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Responsible Party: Royal Liverpool and Broadgreen University Hospitals NHS Trust
ClinicalTrials.gov Identifier: NCT03502291     History of Changes
Other Study ID Numbers: 4896
First Posted: April 18, 2018    Key Record Dates
Last Update Posted: April 18, 2018
Last Verified: May 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Royal Liverpool and Broadgreen University Hospitals NHS Trust:
Human challenge models
Immunity
Streptococcus pneumoniae
Live Attenuated Influenza Vaccine
Additional relevant MeSH terms:
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Tetracycline
Influenza, Human
Pneumonia
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Lung Diseases
Vaccines
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action