A Clinical Challenge Study of BCG in Healthy Volunteers

• ClinicalTrials.gov Identifier: NCT02088892
• Recruitment Status: Completed
• First Posted: March 17, 2014
• Last Update Posted: January 22, 2015
• Sponsor: University of Oxford
• Collaborators: Aeras; University of Birmingham
• Information provided by (Responsible Party): University of Oxford

Tracking Information

• First Submitted Date: March 10, 2014
• First Posted Date: March 17, 2014
• Last Update Posted Date: January 22, 2015
• Study Start Date: March 2014
• Actual Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 14, 2014)

Quantity of BCG at challenge site [ Time Frame: At Day 14 ]

To evaluate and compare the amount of BCG (measured by CFU count and PCR) from a biopsy taken from the intradermal BCG challenge site in healthy BCG-naïve adults receiving either BCG SSI or BCG Tice at either standard or high dose

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 14, 2014)

Immune response markers [ Time Frame: Up to Day 14 ]

To identify laboratory markers of the immune response that correlate with the levels of mycobacterial suppression at the BCG challenge site

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: July 8, 2014)

• Local and systemic adverse events [ Time Frame: Up to Day 28 ]
  To evaluate and compare local and systemic adverse events between the different challenge models through actively and passively collected data on adverse events.
• Mycobacterial Growth Inhibition Assays [ Time Frame: Up to day 14 ]
  Use of Mycobacterial Growth Inhibition Assays to evaluate the effect of recent BCG vaccination on in-vitro ability to control Staphylococcus aureus, and potentially also Klebsiella, Group B streptococcus and Escherichia coli.

Original Other Pre-specified Outcome Measures (submitted: March 14, 2014)

Local and systemic adverse events [ Time Frame: Up to Day 28 ]

To evaluate and compare local and systemic adverse events between the different challenge models through actively and passively collected data on adverse events.

Descriptive Information

• Brief Title: A Clinical Challenge Study of BCG in Healthy Volunteers
• Official Title: A Clinical Challenge Study to Quantify BCG at the Challenge Site of Healthy Volunteers Receiving Either Intradermal BCG SSI or BCG TICE at Standard or High Dose
• Brief Summary: TB031 is a challenge study comparing two different strains of the Bacille Calmette-Guérin (BCG) vaccine at standard and high dose.

Detailed Description

Currently, to assess vaccine efficacy against tuberculosis (TB) there is no alternative to large randomized controlled trials. These efficacy trials for novel TB vaccines are difficult, long and very costly. For this reason there is an urgent need for a valid, reliable, and strong correlate of protection which can help distinguish between candidate TB vaccines undergoing phase I trials, and thereby allow the vaccine development field to advance more quickly, and in a more cost-effective manner.

This study aims to address the current lack of immunological correlates in the TB vaccine field. As an alternative to phase II field trials, human challenge models can provide an evaluation of preliminary efficacy of vaccine candidates. Challenge models, with their concept of deliberate infectious challenge of human volunteers, have been well established for pathogens such as malaria, typhoid and dengue, and these models have greatly facilitated vaccine development. At present there is no safe human challenge model of Mycobacterium tuberculosis (M. tb) infection to enable proof-of-concept efficacy evaluation of candidate vaccines.

Whilst scientists cannot use M. tb as a challenge agent to evaluate efficacy in a clinical trial for safety and ethical reasons, they can use another mycobacterium, attenuated Mycobacterium bovis, as a surrogate for M. tb infection. Attenuated Mycobacterium bovis is the mycobacterial strain in BCG and is safe to use in humans. An effective vaccine against M. tb should also be effective against BCG. After injection into humans, BCG replicates, and an effective TB vaccine should reduce this BCG replication. The BCG challenge model is based on this premise. In the human BCG challenge model, BCG is administered intradermally and the degree of BCG growth suppression is quantified by analysing the tissue obtained in a punch biopsy of volunteers' skin over the BCG 'challenge' site.

This study aims to use two different strains of BCG, each at standard and high dose, to optimise this BCG challenge model.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label)
• Condition: Tuberculosis

Intervention

• Drug: BCG SSI
  Intradermal injection
  Other Name: Bacille Calmette-Guérin Statens Serum Institute (BCG SSI)
• Drug: BCG Tice
  Intradermal injection
  Other Name: Bacille Calmette-Guérin Tice

Study Arms

• Experimental: Group A
  10 BCG-naïve subjects receiving intradermal BCG SSI at standard dose (2-8 x 10^5 cfu) followed by a punch biopsy at the challenge site 14 days later.
  Intervention: Drug: BCG SSI
• Experimental: Group B
  10 BCG-naïve subjects receiving BCG Tice at standard dose (2-8 x 10^5 cfu) followed by a punch biopsy at the challenge site 14 days later.
  Intervention: Drug: BCG Tice
• Experimental: Group C
  10 BCG-naïve subjects receiving intradermal BCG SSI at high dose (6-24 x 10^5 cfu) followed by a punch biopsy at the challenge site 14 days later.
  Intervention: Drug: BCG SSI
• Experimental: Group D
  10 BCG-naïve subjects receiving intradermal BCG Tice at high dose (6-24 x 10^5 cfu) followed by a punch biopsy at the challenge site 14 days later.
  Intervention: Drug: BCG Tice
• Experimental: Group E
  8-12 BCG-naïve subjects receiving the optimal strain and dose of intradermal BCG identified from preliminary results obtained from Group A, B, C and D, followed by a punch biopsy at the challenge site 14 days later.
  Interventions:

  • Drug: BCG SSI
  • Drug: BCG Tice

• Publications *: Minhinnick A, Harris S, Wilkie M, Peter J, Stockdale L, Manjaly-Thomas ZR, Vermaak S, Satti I, Moss P, McShane H. Optimization of a Human Bacille Calmette-Guérin Challenge Model: A Tool to Evaluate Antimycobacterial Immunity. J Infect Dis. 2016 Mar 1;213(5):824-30. doi: 10.1093/infdis/jiv482. Epub 2015 Oct 8.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 8, 2014): 52
• Original Estimated Enrollment (submitted: March 14, 2014): 40
• Actual Study Completion Date: January 2015
• Actual Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Volunteers must meet all of the following criteria to enter the study:

• Healthy adult aged 18-55 years
• BCG naïve
• Resident in or near Oxford (for CCTVM) or Birmingham (for WTCRF) for the duration of the study period
• No relevant findings in medical history or on physical examination
• Allow the Investigators to discuss the volunteer's medical history with their GP
• Use effective contraception for the duration of the study period (females only)
• Agreement to refrain from blood donation during the duration of the study
• Give written informed consent
• Allow the Investigator to register volunteer details with a confidential database to prevent concurrent entry into clinical trials
• Able and willing (in the Investigator's opinion) to comply with all the study requirements

Exclusion Criteria:

Volunteers must meet none of the following criteria to enter the study:

• Laboratory evidence at screening of latent M. tb infection as indicated by a positive ELISPOT response to ESAT6 or CFP10 antigens
• Clinical, radiological, or laboratory evidence of current active TB disease
• Previous vaccination with BCG, or any candidate TB vaccine
• Within the last year had close household contact with an individual with smear positive pulmonary tuberculosis
• Clinically significant history of skin disorder, allergy, immunodeficiency (including HIV), cancer (except BCC or CIS), cardiovascular disease, respiratory disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder, neurological illness, psychiatric disorder, drug or alcohol abuse
• History of serious psychiatric condition
• 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 challenge agent
• Any abnormality of screening blood or urine tests that is deemed to be clinically significant or that may compromise the safety of the volunteer in the study
• Positive HBsAg, HCV or HIV antibodies
• Female confirmed pregnant or intention to become pregnant during study period, or currently lactating
• Current involvement in another trial that involves regular blood tests or an investigational medicinal product
• Use of an investigational medicinal product or non-registered drug, live vaccine, or investigational medical device for four weeks prior to dosing with the study challenge agent
• Administration of immunoglobulins and/or any blood products within the three months preceding the planned challenge date
• Any other significant disease, disorder, or finding, which, in the opinion of the Investigator, may either put the volunteer at risk, or may influence the result of the study, or may affect the volunteer's ability to participate in the study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT02088892
• Other Study ID Numbers: TB031
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: University of Oxford
• Study Sponsor: University of Oxford

Collaborators

• Aeras
• University of Birmingham

Investigators

• Study Director: Helen McShane; University of Oxford

• PRS Account: University of Oxford
• Verification Date: January 2015