A Randomized, Placebo Controlled, Partially Blinded Phase II Study to Evaluate Safety, Immunogenicity, and Prevention of Infection With Mycobacterium Tuberculosis of AERAS-404 and BCG Revaccination in Healthy Adolescents (040-404)
|Tuberculosis||Biological: AERAS-404 Drug: Placebo Biological: Bacillus Calmette-Guérin (BCG)||Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
|Official Title:||A Randomized, Placebo Controlled, Partially Blinded Phase II Study to Evaluate Safety, Immunogenicity, and Prevention of Infection With Mycobacterium Tuberculosis of AERAS-404 and BCG Revaccination in Healthy Adolescents|
- Safety, in HIV-uninfected, remotely BCG vaccinated adolescents, of Aeras-404 or BCG revaccination; measured by the number and percentage of unsolicited and solicited adverse events recorded post vaccination. [ Time Frame: Minimum follow-up time of 6 months ]
- Prevention of Mtb infection, as measured by rates of conversion using a QFT-GIT assay (change from negative to positive), by AERAS-404 compared to placebo or BCG revaccination compared to placebo. [ Time Frame: Minimum follow-up time of 6 months; median follow-up time at least 15 months; and a maximum individual follow-up to QFT-GIT conversion of 24 months. ]
- Prevention of Mtb infection measured by rates of sustained conversion using a QFT-GIT assay, by AERAS-404 compared to placebo, or BCG revaccination compared to placebo. [ Time Frame: Minimum follow-up time of 6 months; median follow-up time at least 15 months; and a maximum individual follow-up to QFT-GIT conversion of 24 months. ]
- Immunogenicity in HIV-uninfected, remotely BCG vaccinated adolescents of AERAS-404 or BCG revaccination. [ Time Frame: Minimum follow-up time of 6 months; median follow-up time at least 15 months; and a maximum individual follow-up to QFT-GIT conversion of 24 months. ]The primary variables of interest for preliminary assessment of immune response to vaccine will be the percentage of CD4+ and CD8+ T cells that express IFN-γ, TNF, IL-2, IL-17, IL-22,CD107a, and/or CD154 alone or in combination in response to stimulation with peptide pools representing the entire amino acid sequence of the mycobacterial antigens Ag85B and TB10.4, and BCG antigens. Due to high backgrounds associated with the CD107a response, CD107a expression in the absence of any other functional response will be ignored. Response will be measured by flow cytometry in the intracellular cytokine staining (ICS) assay.
|Study Start Date:||February 2014|
|Estimated Study Completion Date:||December 2017|
|Estimated Primary Completion Date:||September 2017 (Final data collection date for primary outcome measure)|
Experimental: AERAS-404 (15 mcgH4/500 nmol IC31)
2 doses on Study Days 0 and 56
The H4 antigen is a fusion protein created from two Mtb antigens: antigen Ag85B and TB10.4. Ag85B is also referred to as α-antigen and is a 30-kDa mycolyl transferase protein. TB10.4 is one of three members of the very similar ESAT-6 group of proteins found in Mtb culture supernatants. TB10.4 induces broad immune responses in T cells isolated from TB subjects compared to BCG-vaccinated donors and unvaccinated donors. IC31 is a combination of a leucine-rich peptide named KLK & a synthetic oligonucleotide named ODN1a. The optimal molar ratio of KLK to ODN1a in mice is 25:1. AERAS-404 & saline placebo trial arms will be double-blinded since BCG causes a recognizable local injection site reaction, the BCG revaccination trial arm will be unblinded.
Active Comparator: Bacillus Calmette-Guérin (BCG)
1 Dose on Study Day 0
Biological: Bacillus Calmette-Guérin (BCG)
BCG SSI Vaccine is registered in South Africa for prevention of TB in children and adults. BCG, an attenuated, live culture of the Bacillus Calmette-Guérin, was originally attenuated between 1906 and 1919 by serial passage of an M. bovis strain. The manufacturer Statens Serum Institut (SSI) in Copenhagen, Denmark derives this vaccine from the Danish BCG strain 1331. BCG SSI is supplied by the manufacturer in amber 10-dose vials containing 0.75 mg lyophilized SSI BCG. The BCG revaccination trial arm will be unblinded (open label).
Placebo Comparator: Placebo
2 Doses on Study Days 0 and 56
Tris buffered saline (10mM Tris,pH 7.4, 150NM sodium chloride)
Other Name: Tris buffered saline
This Phase II, randomized, 3-arm, placebo controlled, partially blinded, clinical trial will be conducted in 990 healthy, HIV-uninfected, QFT-GIT negative, previously BCG vaccinated adolescents. The trial will be conducted at the South African Tuberculosis Vaccine Initiative (SATVI) site in the Western Cape region of South Africa, where epidemiological studies involving thousands of adolescents have been conducted over the last decade to characterize rates of Mtb infection and active TB disease in this age group. Subjects will be enrolled in two sequential cohorts and within each cohort subjects will be randomized in a 1:1:1 ratio to receive either AERAS-404 or saline placebo on Days 0 and 56, or BCG Vaccine SSI on Day 0. The first 90 subjects (30 from each arm) will form the Safety & Immunogenicity Cohort and will be subject to more intensive collection of safety data, with data reviewed by the Data Monitoring Committee (DMC), principal investigator and local medical monitor. Selected immunogenicity assays, including whole blood intracellular cytokine staining (ICS), will also be performed in this cohort. The remaining 900 subjects will be enrolled into the Correlates Cohort. All 990 subjects in the study will be evaluated for safety and biomarker outcomes, and for prevention of Mtb infection.
The primary Mtb infection endpoint will be QFT-GIT conversion from a negative to positive test, using the manufacturer's recommended threshold of 0.35 IU/mL, at any time-point after Day 84 and through end of follow-up for the primary endpoint. The 84-day 'wash-out' period is stipulated in order to exclude subjects who may have already been Mtb infected, but not yet converted their QFT-GIT test at screening, thus subjects who convert their QFT-GIT at Day 84 will not be included in the analyses of prevention of Mtb infection.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02075203
|South African Tuberculosis Vaccine Initiative , Project Office, Brewelskloof Hospital , Harlem Street, Worcester|
|Cape Town, Western Cape, South Africa, 6850|
|Desmond Tutu HIV Foundation (DTHF)|
|Nyanga, South Africa|
|Study Director:||Robert Hopkins, MD||Aeras|
|Principal Investigator:||Mark Hatherill||The South African Tuberculosis Vaccine Initiative(SATVI)|