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Investigating Immune Responses to Aerosol BCG Challenge in Healthy UK Adults

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ClinicalTrials.gov Identifier: NCT03912207
Recruitment Status : Recruiting
First Posted : April 11, 2019
Last Update Posted : October 3, 2019
Sponsor:
Collaborators:
Wellcome Trust
National Institute for Health Research, United Kingdom
Information provided by (Responsible Party):
University of Oxford

Brief Summary:
TB043 is a clinical challenge trial primarily to evaluate the safety of BCG challenge administered by the aerosol inhaled route in healthy, BCG naive UK adults. The trial will also look to evaluate and compare the amount of BCG recovered from the lungs as various points after challenge.

Condition or disease Intervention/treatment Phase
Tuberculosis Biological: BCG Danish Other: Saline placebo Phase 1

Detailed Description:

Mycobacterium tuberculosis (M.tb) is a pathogen with worldwide preponderance that infects humans and causes the transmissible disease tuberculosis (TB). An estimated one-third of the world's population is latently infected with M.tb, carrying a 10% lifetime risk of developing active life-threatening disease. In 2016, there were 10 million new cases worldwide and 1.7 million people died of TB. Co-infection with human immunodeficiency virus (HIV) greatly increases the risk of TB reactivation and death. Diagnosis is challenging and drug treatment is often harmful, costly and complex. For these reasons, it is essential to develop a more effective vaccine against TB.

An improved understanding of the nature of protective immunity in humans would significantly improve rational vaccine development. Whilst host immunity, particularly systemic adaptive immunity, has been well characterized in murine models, the understanding of the immunological events that occur in humans during acute infection is limited. In particular, the knowledge of human mucosal responses to M.tb. is limited. This is primarily due to the difficulties in studying early disease processes in the lung. Consequently, the majority of human studies have investigated immune responses ex-vivo in peripheral blood or after in-vitro infection of cell lines. A better understanding of the immune components that exist at the respiratory mucosal surfaces in humans could lead to interventions that prevent infection at the point of entry.

TB043 is a clinical challenge trial primarily to evaluate the safety of BCG challenge administered by the aerosol inhaled route in healthy, BCG naive UK adults. The trial will also look to evaluate and compare the amount of BCG recovered from the lungs as various points after challenge, allowing investigation into the immune components at mucosal surfaces.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 65 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Masking Description:

Volunteers will be blinded to eliminate subject bias (either conscious or subconscious) using a 10:3 randomised control design (BCG:placebo) whereby volunteers randomised to the BCG arms (Arm A) will inhale aerosolised BCG mixed with normal saline and those randomised to the placebo arms (Arm B) will inhale aerosolised normal saline.

The bronchoscopist performing the procedure will also be blinded to eliminate any bias in the reporting of the appearance of the lung mucosa and extent of airway inflammation.

All samples will be anonymised and the subject number will be allocated sequentially and therefore not identifiable with the allocated Arm. The senior immunologist will be blinded to reduce any bias that could be introduced at the sample processing stage.

Primary Purpose: Other
Official Title: A Human Challenge Study to Evaluate Innate and Adaptive Immune Responses to a Controlled Human Infection With BCG Administered by the Aerosol Inhaled Route in Healthy, BCG-naïve, UK Adult Volunteers
Actual Study Start Date : April 19, 2019
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Experimental: Group 1, 2 Day Bronchoscopy
Group 1: 10 volunteers will receive 1 x 107 cfu aerosol inhaled BCG and 3 volunteers will receive aerosol inhaled normal saline placebo. All Group 1 volunteers will have a bronchoscopy 2 days post challenge
Biological: BCG Danish
BCG Danish 1331 is on the WHO list of pre-qualified vaccines and has a well-defined side effect profile. BCG is licensed for delivery via the intradermal route. It is not licensed for delivery via the aerosol route.

Other: Saline placebo
Saline is a routinely used placebo.

Experimental: Group 2, 7 Day Bronchoscopy
Group 2: 10 volunteers will receive 1 x 107 cfu aerosol inhaled BCG and 3 volunteers will receive aerosol inhaled normal saline placebo. All Group 2 volunteers will have a bronchoscopy 7 days post challenge
Biological: BCG Danish
BCG Danish 1331 is on the WHO list of pre-qualified vaccines and has a well-defined side effect profile. BCG is licensed for delivery via the intradermal route. It is not licensed for delivery via the aerosol route.

Other: Saline placebo
Saline is a routinely used placebo.

Experimental: Group 3, 14 Day Bronchoscopy
Group 3: 10 volunteers will receive 1 x 107 cfu aerosol inhaled BCG and 3 volunteers will receive aerosol inhaled normal saline placebo. All Group 3 volunteers will have a bronchoscopy 14 days post challenge
Biological: BCG Danish
BCG Danish 1331 is on the WHO list of pre-qualified vaccines and has a well-defined side effect profile. BCG is licensed for delivery via the intradermal route. It is not licensed for delivery via the aerosol route.

Other: Saline placebo
Saline is a routinely used placebo.

Experimental: Group 4, 28 Day Bronchoscopy
Group 4: 10 volunteers will receive 1 x 107 cfu aerosol inhaled BCG and 3 volunteers will receive aerosol inhaled normal saline placebo. All Group 4 volunteers will have a bronchoscopy 28 days post challenge
Biological: BCG Danish
BCG Danish 1331 is on the WHO list of pre-qualified vaccines and has a well-defined side effect profile. BCG is licensed for delivery via the intradermal route. It is not licensed for delivery via the aerosol route.

Other: Saline placebo
Saline is a routinely used placebo.

Experimental: Group 5, 56 Day Bronchoscopy
Group 5: 10 volunteers will receive 1 x 107 cfu aerosol inhaled BCG and 3 volunteers will receive aerosol inhaled normal saline placebo. All Group 5 volunteers will have a bronchoscopy 56 days post challenge
Biological: BCG Danish
BCG Danish 1331 is on the WHO list of pre-qualified vaccines and has a well-defined side effect profile. BCG is licensed for delivery via the intradermal route. It is not licensed for delivery via the aerosol route.

Other: Saline placebo
Saline is a routinely used placebo.




Primary Outcome Measures :
  1. Identification of markers of innate immunity-cytokines [ Time Frame: Up to day 168 ]
    Established markers of innate immunity in blood, BAL and biopsy samples will be aggregated to determine overall characterisation of innate response. Specifically, cytokine levels will be measured by ELISpot and ELISA.

  2. Identification of markers of innate immunity-antigen presenting cells [ Time Frame: Up to day 168 ]
    Established markers of innate immunity in blood, BAL and biopsy samples will be aggregated to determine overall characterisation of innate response. Specifically, the activity of antigen presenting cells will be measured by flow.

  3. Identification of markers of innate immunity-inflammation in tissue [ Time Frame: Up to day 168 ]
    Established markers of innate immunity in blood, BAL and biopsy samples will be aggregated to determine overall characterisation of innate response. Specifically IHC staining will be done to examine changes in tissue samples.

  4. Identification of markers of adaptive immunity-antibodies [ Time Frame: Up to day 168 ]
    Established markers of adaptive immunity in blood, BAL and biopsy samples will be aggregated to determine overall characterisation of adaptive response. Specifically, the presence of antibodies will be measured.

  5. Identification of markers of adaptive immunity-T cells [ Time Frame: Up to day 168 ]
    Established markers of adaptive immunity in blood, BAL and biopsy samples will be aggregated to determine overall characterisation of adaptive response. Specifically, T-cell activity will be determined by a flow cytometry panel.


Secondary Outcome Measures :
  1. Mycobacterial growth inhibition assay [ Time Frame: Up to day 56 ]
    MGIA outcome on PBMCs collected at Day 56; readout in CFUs (colony forming units)


Other Outcome Measures:
  1. Adverse Events (AEs) [ Time Frame: Up to day 168 ]
    Collection of AE data at each visit and via diary card, and laboratory parameters of BCG cfu counts in induced sputum



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • Healthy adult aged 18-50 years
  • Resident in or near Oxford for the duration of the study period
  • Screening IGRA negative
  • No relevant findings in medical history or on physical examination
  • Allow the Investigators to discuss the individual's medical history with their GP
  • Use effective contraception (see below) for the duration of the study period (females only)
  • Refrain from blood donation during the study
  • Give written informed consent
  • Allow the Investigator to register volunteer details with a confidential database (The Over-volunteering Protection Service) to prevent concurrent entry into clinical studies/trials
  • Able and willing (in the Investigator's opinion) to comply with all the study requirements

Exclusion Criteria:

  • Previously resident for more than 12 months concurrently in a tropical climate where significant non-tuberculous mycobacterial exposure is likely
  • Participation in another research study involving receipt of an investigational product in the 30 days preceding enrolment, or planned use during the study period
  • Prior vaccination with BCG or any candidate TB vaccine
  • Administration of immunoglobulins and/or any blood products within the three months preceding the planned study challenge date
  • Clinically significant history of skin disorder, allergy, atopy, immunodeficiency (including HIV), cancer (except BCC or CIS), cardiovascular disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder, neurological illness, psychiatric disorder, drug or alcohol abuse
  • Concurrent oral, inhaled or systemic steroid medication or the concurrent use of other immunosuppressive agents
  • Shares a household with someone with clinically significant immunodeficiency (either from infection or medication) who is deemed to be at risk of developing disseminated BCG infection if exposed to BCG
  • History of anaphylaxis to vaccination or any allergy likely to be exacerbated by any component of the study agent, sedative drugs, or any local or general anaesthetic agents
  • Pregnancy, lactation or intention to become pregnant during study period
  • Any respiratory disease, including asthma
  • Current smoker (defined as any smoking including e-cigarettes in the last 3 months)
  • Clinically significant abnormality on screening chest radiograph
  • Clinically significant abnormality of pulmonary function
  • Any nasal, pharyngeal, or laryngeal finding which precludes bronchoscopy
  • Current use of any medication taken through the nasal or inhaled route including cocaine or other recreational drugs
  • Clinical, radiological, or laboratory evidence of current active TB disease
  • Past treatment for TB disease
  • Any clinically significant abnormality of screening blood or urine tests
  • Positive HBsAg, HCV or HIV antibodies
  • Any other significant disease, disorder, or finding, which, in the opinion of the Investigator, may either put the volunteer at risk, affect the volunteer's ability to participate in the study or impair interpretation of the study data

Female volunteers are required to use an effective form of contraception during the course of the study.

Acceptable forms of contraception for female volunteers include:

  • Established use of oral, injected on implanted hormonal methods of contraception
  • Placement of an intrauterine device (IUD) or intrauterine system (IUS)
  • Permanent sterilisation or bilateral tubal occlusion
  • Barrier methods of contraception (condom; or occlusive cap with spermicide)
  • Male sterilisation, if the vasectomised partner is the sole partner for the subject
  • True abstinence, when this is in line with the preferred and usual lifestyle of the subject (periodic abstinence and withdrawal are not acceptable methods of contraception)

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): NCT03912207


Contacts
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Contact: Julia Marshall 01865 611413 julia.marshall@ndm.ox.ac.uk

Locations
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United Kingdom
Centre for Clinical Vaccinology and Tropical Medicine (CCVTM), Churchill Hospital Recruiting
Oxford, Oxfordshire, United Kingdom, OX3 7LE
Contact: Volunteer Coordinator    01865 611421    vaccinetrials@ndm.ox.ac.uk   
Principal Investigator: Helen McShane         
Oxford University Hospitals- John Warin Ward, University of Oxford Recruiting
Oxford, Oxfordshire, United Kingdom, OX3 7LE
Contact: Volunteer Coordinator    01865 611421    vaccinetrials@ndm.ox.ac.uk   
Principal Investigator: Helen McShane         
Sponsors and Collaborators
University of Oxford
Wellcome Trust
National Institute for Health Research, United Kingdom
Investigators
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Principal Investigator: Professor Helen McShane University of Oxford
  Study Documents (Full-Text)

Documents provided by University of Oxford:

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Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT03912207     History of Changes
Other Study ID Numbers: TB043
First Posted: April 11, 2019    Key Record Dates
Last Update Posted: October 3, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Oxford:
BCG
Aerosol
Tuberculosis
Challenge
Additional relevant MeSH terms:
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Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections