A Phase 2b, double-blind, randomized, placebo-controlled study to evaluate the efficacy, safety and immunogenicity of a candidate tuberculosis (TB) vaccine, MTBVAC, against TB disease in adolescents and adults aged 14-45 years, living in a TB endemic region.
Phase 2b, double-blind, randomized, placebo-controlled, safety and efficacy study in 5,500 healthy adults and adolescents. Participants will be enrolled based on IGRA status at baseline into an IGRA-positive cohort (n=4,300) or an IGRA-negative cohort (n=1,200). Most participants are likely to have received previous BCG vaccination in infancy. The investigational product is MTBVAC administered intradermally at 5x105 CFU. Participants meeting the enrolment criteria will be randomized, in a 1:1 ratio if baseline IGRA-positive or in a 3:1 ratio if baseline IGRA-negative, to receive a single dose of MTBVAC or placebo administered intradermally on Study Day 1. Participants will be followed up for efficacy following vaccination via regular visits or contacts to screen for possible TB. Participants will also be trained to recognize signs and symptoms consistent with pulmonary TB disease and to report them for clinical evaluation. Participants with clinical presumption of pulmonary TB will be assessed with confirmatory diagnostic testing using a Nucleic Acid Amplification Test (Xpert MTB/RIF Ultra assay) and microbiological culture in sputum sampled on 3 separate days within a 1 week period. Participants diagnosed with pulmonary TB will be referred for TB treatment according to local clinical practice. Only HIV-negative participants will be eligible for enrolment. Participants will be tested for HIV seroconversion at the end of each year of follow-up and at the presumptive TB visits. Participants who test positive for HIV will be referred for TB preventive treatment and antiretroviral treatment according to local clinical practice. A safety sub-cohort of approximately 660 participants (330 in each study arm) from the IGRA-positive cohort and 225 participants (150 MTBVAC and 75 placebo recipients) from the IGRA-negative cohort will be randomly selected for follow-up for solicited adverse events (AEs) and selected biochemistry and haematology. Additionally, an immunogenicity sub-cohort of approximately 90 participants (60 in the MTBVAC and 30 in the placebo arm) from the IGRA-positive cohort and 90 participants (60 in the MTBVAC and 30 in the placebo arm) from the IGRA-negative cohort will be randomly selected for specific immunogenicity assessments. All participants in the immunogenicity sub-cohort will participate in the safety sub-cohort. The sub-cohort randomization procedures will attempt to evenly distribute participants between adolescents (i.e., age 14 through 17) and adults (i.e., age 18 through 45) and among clinical research centres. The strategy for participant sub-cohort selection and randomization will be described in the Study Operations Manual (SOM) and Statistical Analysis Plan (SAP).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
5,500
Victoria Biomedical Research Institute
Kisumu, Kenya
Kenya Medical Research Institute
Nairobi, Kenya
To evaluate the protective efficacy of MTBVAC against bacteriologically confirmed PTB, not associated with HIV infection, diagnosed by more than one diagnostic test with sputum obtained before initiation of TB treatment, in baseline IGRA-positives.
Incident cases of definite pulmonary TB disease in baseline IGRA-positive participants with clinical suspicion of pulmonary TB disease, with Mtb identified by at least two positive diagnostic tests (two positive microbiological cultures or two positive Xpert MTB/RIF Ultra assays, or one positive of each) from sputum specimens taken before initiation of TB treatment and confirmed HIV-negative at the time of TB diagnosis, over a period starting 28 days following vaccination and lasting up to 36 months post vaccination.
Time frame: 36 Months
To evaluate the protective efficacy of one dose of MTBVAC against bacteriologically confirmed pulmonary TB disease, not associated with HIV infection, diagnosed by more than one diagnostic test with sputum obtained before initiation of TB treatment.
Incident cases of definite pulmonary TB disease in baseline IGRA-positive and IGRA-negative participants with clinical suspicion of pulmonary TB disease, with M.tb identified by at least two positive diagnostic tests (two positive microbiological cultures or two positive Xpert MTB/RIF Ultra assays, or one positive of each) from sputum specimens taken before initiation of TB treatment and confirmed HIV-negative at the time of TB diagnosis, over a period starting 28 days following vaccination and lasting up to 36 months post-vaccination.
Time frame: 36 Months
To evaluate the protective efficacy of one dose of MTBVAC against bacteriologically confirmed pulmonary TB disease, not associated with HIV infection, diagnosed with sputum obtained before initiation of TB treatment, as compared to placebo.
Incident cases of definite pulmonary TB disease in baseline IGRA-positive and IGRA-negative participants with clinical suspicion of pulmonary TB disease, with M.tb identified by microbiological culture or Xpert MTB/RIF Ultra from sputum specimens taken before initiation of TB treatment and confirmed HIV-negative at the time of TB diagnosis, over a period starting 28 days following vaccination and lasting up to 36 months post-vaccination.
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JOSHA Research
Bloemfontein, South Africa
South African Tuberculosis Vaccine Initiative
Cape Town, South Africa
TASK Applied Science Pty Ltd. TASK Delft
Cape Town, South Africa
UCTLI CLII - Centre for Lung Infection and Immunity
Cape Town, South Africa
University of Cape Town Lung Institute PtyLtd. Centre for Tuberculosis Research Innovation
Cape Town, South Africa
Wellcome Centre for Infectious Diseases Research in Africa
Cape Town, South Africa
Synergy Biomedical Research Institute
East London, South Africa
TASK Eden Pty Ltd.
George, South Africa
...and 6 more locations
Time frame: 36 months
To evaluate the protective efficacy of one dose of MTBVAC against definite Xpert MTB/RIF Ultra positive pulmonary TB disease not associated with HIV infection, diagnosed with sputum obtained before initiation of TB treatment, as compared to placebo.
Incident cases of definite pulmonary TB disease in baseline IGRA-positive and IGRA-negative participants with clinical suspicion of pulmonary TB disease, with M.tb identified by Xpert MTB/RIF Ultra from sputum specimens taken before initiation of TB treatment and confirmed HIV-negative at the time of TB diagnosis, over a period starting 28 days following vaccination and lasting up to 36 months post-vaccination.
Time frame: 36 months
To evaluate the protective efficacy of one dose of MTBVAC against clinical TB, as compared to placebo, in the entire study population.
Incident cases of clinical TB disease in baseline IGRA-positive and IGRA-negative participants diagnosed by a clinician who has decided to treat the participant with TB treatment, over a period starting 28 days following vaccination and lasting up to 36 months post-vaccination.
Time frame: 36 Months
To assess the safety and reactogenicity of one dose of MTBVAC, overall and stratified by IGRA status at baseline.
The proportion of participants with SAEs until Month 6 following vaccination.
Time frame: 6 months
To assess the safety and reactogenicity of one dose of MTBVAC, overall and stratified by IGRA status at baseline.
The proportion of participants with vaccine related SAEs during the entire study period.
Time frame: 36 months
To assess the safety and reactogenicity of one dose of MTBVAC, overall and stratified by IGRA status at baseline.
The proportion of participants with solicited injection site reactions and solicited systemic AEs in the safety sub-cohort during the 14 days following vaccination (day of vaccination and 14 subsequent days).
Time frame: 28 Days
To assess the safety and reactogenicity of one dose of MTBVAC, overall and stratified by IGRA status at baseline.
The proportion of participants with unsolicited AEs during the 28 days following vaccination (day of vaccination and 28 subsequent days).
Time frame: 56 Days
To assess the safety and reactogenicity of one dose of MTBVAC, overall and stratified by IGRA status at baseline.
The proportion of participants with unsolicited injection site reactions during the 84 days following vaccination (day of vaccination and 84 subsequent days).
Time frame: 168 days
To assess the safety and reactogenicity of one dose of MTBVAC, overall and stratified by IGRA status at baseline.
The proportion of participants with grade 3 or higher injection site reactions during the 84 days following vaccination (day of vaccination and 84 subsequent days).
Time frame: 168 days
To assess the safety and reactogenicity of one dose of MTBVAC, overall and stratified by IGRA status at baseline.
The proportion of participants with grade 2 or higher haematological and biochemical laboratory AEs, in the safety sub-cohort.
Time frame: 36 months
To assess the safety and reactogenicity of one dose of MTBVAC, overall and stratified by IGRA status at baseline.
The proportion of participants with AESIs until Month 6 following vaccination.
Time frame: 6 months
To assess the immunogenicity of one dose of MTBVAC via assessment of cell-mediated immune (CMI) responses in a subset of the enrolled participants, overall and stratified by IGRA status at baseline (immunogenicity sub-cohort only).
Evaluation of CMI responses with respect to components of the study vaccine, in the immunogenicity sub-cohort at Day 1 (prior to vaccination), Day 29, Month 12, Month 24 and Month 36 (if applicable).
Time frame: 36 months