Investigating Immune Responses to Aerosol BCG Challenge in Healthy UK Adults

NCT03912207 | Unknown Phase 1

• 1 other identifier: TB043
• Study Type: interventional
• Target: 94
• Locations: 1 country
• Sites: 2

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 (Group 1-7) as well as historically BCG vaccinated UK adults (Group 8) . The trial will also look to evaluate and compare the amount of BCG recovered from the lungs as various points after challenge.

Conditions

Tuberculosis

Keywords

BCG; Aerosol; Tuberculosis; Challenge

Outcome Measures

Primary Outcomes (5)

• Identification of markers of innate immunity-cytokines

  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.

  Up to day 168

• Identification of markers of innate immunity-antigen presenting cells

  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 cytometry

  Up to day 168

• Identification of markers of innate immunity-inflammation in tissue

  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.

  Up to day 168

• Identification of markers of adaptive immunity-antibodies

  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.

  Up to day 168

• Identification of markers of adaptive immunity-T cells

  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.

  Up to day 168

Secondary Outcomes (1)

• Mycobacterial growth inhibition assay

  Up to day 56

Other Outcomes (1)

• Adverse Events (AEs)

  Up to day 168

Study Arms (8)

Group 1, 2 Day Bronchoscopy

EXPERIMENTAL

Group 1: 10 volunteers will receive 1 x 10\^7 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; Other: Saline placebo

Group 2, 7 Day Bronchoscopy

EXPERIMENTAL

Group 2: 10 volunteers will receive 1 x 10\^7 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; Other: Saline placebo

Group 3, 14 Day Bronchoscopy

EXPERIMENTAL

Group 3: 10 volunteers will receive 1 x 10\^7 cfu aerosol inhaled BCG (Arm A) and 3 volunteers will receive aerosol inhaled normal saline placebo (Arm B). All Group 3 volunteers will have a bronchoscopy 14 days post challenge Volunteers in group 7 and group 3 (arm A) will be offered an optional follow up at 12 months, in order of enrolment until 10 such visits have been conducted. For group 3 volunteers this will be offered after unblinding.

Biological: BCG Danish; Other: Saline placebo

Group 4, 28 Day Bronchoscopy

EXPERIMENTAL

Group 4: 10 volunteers will receive 1 x 10\^7 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; Other: Saline placebo

Group 5, 56 Day Bronchoscopy

EXPERIMENTAL

Group 5: 10 volunteers will receive 1 x 10\^7 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; Other: Saline placebo

Group 6, Intradermal injection, 14 Day Bronchoscopy

EXPERIMENTAL

Group 6: 6 volunteers will receive 1 x 10\^6 cfu intradermal injection BCG + aerosol saline and will have a bronchoscopy 14 days post challenge All volunteers in group 6 will be offered an optional follow up at 12 months

Biological: BCG Danish; Other: Saline placebo

Group 7, 14 Day Bronchoscopy

EXPERIMENTAL

Group 7: 10 volunteers will receive 1 x 10\^7cfu aerosol inhaled BCG. All Group 7 volunteers will have a bronchoscopy 14 days post challenge. Volunteers in group 7 and group 3 (arm A) will be offered an optional follow up at 12 months, in order of enrolment until 10 such visits have been conducted

Biological: BCG Danish

Group 8, Bronchoscopy Day 14

EXPERIMENTAL

Group 8: 10 historically BCG vaccinated volunteers will receive aerosol inhaled BCG at a dose to be confirmed from emerging study data TB044 (Clinicaltrials.gov NCT04777721). All Group 8 volunteers will have a bronchoscopy 14 days post challenge.

Biological: BCG Danish

Interventions

BCG Danish BIOLOGICAL

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.

Group 1, 2 Day Bronchoscopy; Group 2, 7 Day Bronchoscopy; Group 3, 14 Day Bronchoscopy; Group 4, 28 Day Bronchoscopy; Group 5, 56 Day Bronchoscopy; Group 6, Intradermal injection, 14 Day Bronchoscopy; Group 7, 14 Day Bronchoscopy; Group 8, Bronchoscopy Day 14

Saline placebo OTHER

Saline is a routinely used placebo.

Group 1, 2 Day Bronchoscopy; Group 2, 7 Day Bronchoscopy; Group 3, 14 Day Bronchoscopy; Group 4, 28 Day Bronchoscopy; Group 5, 56 Day Bronchoscopy; Group 6, Intradermal injection, 14 Day Bronchoscopy

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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 (people of child bearing potential 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
• Willing to be tested for evidence of SARS-CoV-2 infection, if indicated and to allow public health notification of results if required.
• Able and willing (in the Investigator's opinion) to comply with all the study requirements
• For Group 8 only- previously vaccinated with BCG (at least 12 months prior to enrolment, as evidenced by a visible scar or documentation in medical or occupational health records)

You may not qualify if:

• Previously resident for more than 12 months concurrently in a rural area of 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 (G1-7 only) or any other candidate TB vaccine (all groups).
• 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, essential study procedures, sedative drugs, or any local or general anaesthetic agents
• Pregnancy, lactation or intention to become pregnant during study period
• Any clinically significant 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

Sponsors & Collaborators

• University of Oxford: lead
• Wellcome Trust: collaborator
• National Institute for Health Research, United Kingdom: collaborator
• University of Leicester: collaborator

Study Sites (2)

Centre for Clinical Vaccinology and Tropical Medicine (CCVTM), Churchill Hospital

Oxford, Oxfordshire, OX3 7LE, United Kingdom

Location

Oxford University Hospitals- John Warin Ward, University of Oxford

Oxford, Oxfordshire, OX3 7LE, United Kingdom

Location

MeSH Terms

Conditions

Tuberculosis

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Study Officials

• Professor Helen McShane

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: Volunteers in groups 1-5 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 volunteers will be unblinded just prior to the 3 month visit when those in Arm A may have sputum collected and those in Arm B will not. Volunteers in group 6 and 8 will not be blinded. For groups 1 -5, 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.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 30, 2019
• First Posted: April 11, 2019
• Study Start: April 19, 2019
• Primary Completion: June 1, 2024
• Study Completion: June 1, 2024
• Last Updated: January 3, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2)