Aerosol BCG Challenge Trial in Healthy UK Adults

A Clinical Challenge Trial to Evaluate Controlled Human Infection With BCG Administered by the Aerosol Inhaled Route Compared With the Intradermal Route in Healthy, BCG-naïve, UK Adult Volunteers

TB041 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 and from the skin, following challenge by either the aerosol or the intradermal route.

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Other: Saline placebo; Biological: BCG; Biological: BCG

Detailed Description

Mycobacterium tuberculosis (M.tb) is a pathogen found worldwide that infects humans causing tuberculosis (TB), a transmissible disease resulting in very high mortality and morbidity. It is estimated that a third of the world's population is latently infected with M.tb, and these people carry a 10% lifetime risk of developing active life-threatening disease. In 2013, there were 9 million new cases worldwide and 1.5 million people died of TB. Co-infection with human immunodeficiency virus (HIV) greatly increases risk of TB reactivation and death. TB diagnosis is challenging and drug treatment can be prolonged, harmful, costly and complex. For these reasons an effective vaccine is a global public health priority.

Currently to assess vaccine efficacy against TB there is no reliable alternative to large, randomized controlled trials. These efficacy trials for novel TB vaccines are challenging, time consuming and very costly. For other diseases, such as malaria, challenge studies have been informative. The development of a safe controlled human mycobacterial challenge model which would ultimately be validated against field efficacy studies could greatly facilitate TB vaccine development by being a guide for selecting which candidate TB vaccines to take forwards to large efficacy trials.

TB041 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 and from the skin, following challenge by either the aerosol or the intradermal route.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 7LE
      • Centre for Clinical Vaccinology and Tropical Medicine , University of Oxford
    • Oxford, Oxfordshire, United Kingdom, OX3 7LE
      • Oxford University Hospitals- John Warin Ward, University of Oxford
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2TH
      • NIHR Wellcome Trust Clinical Research Facility, University of Birmingham

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy adult aged 18-50 years
• Resident in or near Oxford (CCVTM or OUH) or Birmingham (NIHR-WTCRF) for the = duration of the trial period
• Screening IGRA negative
• Chest radiograph normal
• 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 trial period (females only)
• Refrain from blood donation during the trial
• 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 trial 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 trial involving receipt of an investigational product in the 30 days preceding enrolment, or planned use during the trial 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 trial 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 or systemic steroid medication or the concurrent use of other immunosuppressive agents
• History of anaphylaxis to vaccination or any allergy likely to be exacerbated by any component of the trial agent, sedative drugs, or any local or general anaesthetic agents
• Pregnancy, lactation or intention to become pregnant during trial period Any respiratory disease, including asthma
• Current smoker
• Clinically significant abnormality on screening chest radiograph
• Clinically significant abnormality of spirometry
• 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 trial or impair interpretation of the trial data

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Group 1A: low dose aerosol BCG SSI; 3 volunteers receiving BCG SSI at a dose of 1 x 10^3 cfu by the aerosol inhaled route, followed by bronchoscopy.	Biological: BCG; BCG SSI (Due to a global shortage of BCG SSI, BCG Bulgaria used in Group 2); Biological: BCG; BCG Bulgaria (InterVax)
Other: Group 1B: medium dose aerosol BCG SSI; 3 volunteers receiving BCG SSI at a dose of 1 x 10^4 cfu by the aerosol inhaled route, followed by bronchoscopy.	Biological: BCG; BCG SSI (Due to a global shortage of BCG SSI, BCG Bulgaria used in Group 2); Biological: BCG; BCG Bulgaria (InterVax)
Experimental: Group 1C: standard dose aerosol BCG SSI; 12 volunteers receiving BCG SSI at a dose of 1 x 10^5 cfu by the aerosol inhaled route and intradermal saline placebo, followed by bronchoscopy.	Other: Saline placebo; Saline placebo; Biological: BCG; BCG SSI (Due to a global shortage of BCG SSI, BCG Bulgaria used in Group 2); Biological: BCG; BCG Bulgaria (InterVax)
Experimental: Group 1D: standard dose intradermal BCG SSI; 12 volunteers receiving BCG SSI at a dose of 1 x 10^5 cfu by the intradermal route and aerosol inhaled saline placebo, followed by bronchoscopy and punch biopsy at the intradermal injection site.	Other: Saline placebo; Saline placebo; Biological: BCG; BCG SSI (Due to a global shortage of BCG SSI, BCG Bulgaria used in Group 2); Biological: BCG; BCG Bulgaria (InterVax)
Other: Group 2A: lower than standard dose aerosol BCG Bulgaria; 3 volunteers receiving BCG Bulgaria (InterVax) at a dose of 1 x 10^4 cfu by the aerosol inhaled route, followed by bronchoscopy.	Biological: BCG; BCG SSI (Due to a global shortage of BCG SSI, BCG Bulgaria used in Group 2); Biological: BCG; BCG Bulgaria (InterVax)
Other: Group 2B: close to the standard dose aerosol BCG Bulgaria; 3 volunteers receiving BCG Bulgaria (InterVax) at a dose of 1 x 10^5 cfu by the aerosol route, followed by bronchoscopy.	Biological: BCG; BCG SSI (Due to a global shortage of BCG SSI, BCG Bulgaria used in Group 2); Biological: BCG; BCG Bulgaria (InterVax)
Other: Group 2C: higher than standard dose aerosol BCG Bulgaria; 3 volunteers receiving BCG Bulgaria (InterVax) at a dose of 1 x 10^6 cfu by the aerosol inhaled route, followed by bronchoscopy.	Biological: BCG; BCG SSI (Due to a global shortage of BCG SSI, BCG Bulgaria used in Group 2); Biological: BCG; BCG Bulgaria (InterVax)
Experimental: Group 2D: close to or higher than standard aerosol BCG; 3 volunteers receiving 1 x 10^7 cfu aerosol inhaled BCG Bulgaria (InterVax), followed by bronchoscopy 14 days later	Biological: BCG; BCG SSI (Due to a global shortage of BCG SSI, BCG Bulgaria used in Group 2); Biological: BCG; BCG Bulgaria (InterVax)
Experimental: Group 2E: close to or higher than standard intradermal BCG; 9 volunteers receiving the optimal dose of aerosol inhaled BCG Bulgaria (InterVax) identified from preliminary results obtained from Groups 2C and 2D, and ID saline placebo, followed by bronchoscopy 14 days later	Other: Saline placebo; Saline placebo; Biological: BCG; BCG SSI (Due to a global shortage of BCG SSI, BCG Bulgaria used in Group 2); Biological: BCG; BCG Bulgaria (InterVax)
Experimental: Group 2F: 1 log lower than Group 2E; 12 volunteers will receive aerosol inhaled saline placebo and intradermal BCG Bulgaria (InterVax), at a dose a log lower than 2E then bronchoscopy and punch biopsy	Other: Saline placebo; Saline placebo; Biological: BCG; BCG SSI (Due to a global shortage of BCG SSI, BCG Bulgaria used in Group 2); Biological: BCG; BCG Bulgaria (InterVax)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events (AE)	Collection of AE data at each visit and via diary card for 28 days after challenge.	Up to day 168

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantification of BCG	Quantification of BCG in bronchoalveolar lavage (BAL) sample and intradermal biopsy sample.	At day 14

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of cellular markers of immunity	Established and exploratory markers of innate, cell mediated and humoral immunity in blood and BAL samples will be used to identify cellular markers of immunity to BCG.	Up to day 168
Evaluation of aerosol BCG challenge vs intradermal BCG challenge	Laboratory markers of cell mediated and humoral immunity, including ex-vivo ELISpot in blood and intracellular cytokine staining in blood and BAL samples will be used to assess which route of challenge is most effective	Up to day 168

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: University of Birmingham
• Investigators: Principal Investigator: Professor Paul Moss, University of Birmingham; Principal Investigator: Professor Helen McShane, University of Oxford

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2016
• Primary Completion (Actual): May 9, 2019
• Study Completion (Actual): May 9, 2019

Study Registration Dates

• First Submitted: February 12, 2016
• First Submitted That Met QC Criteria: March 9, 2016
• First Posted (Estimated): March 16, 2016

Study Record Updates

• Last Update Posted (Estimated): November 17, 2023
• Last Update Submitted That Met QC Criteria: November 14, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Tuberculosis; BCG; Aerosol; Challenge
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: TB041

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED