Tuberculosis
Conditions
Keywords
BCG Vaccinated
Brief summary
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
Detailed description
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.
Interventions
BIOLOGICALAERAS-404
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.
DRUGPlacebo
Saline
BIOLOGICALBacillus 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).
Sponsors
Sanofi Pasteur, a Sanofi Company
Aeras
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
Yes
Inclusion criteria
1. Has completed the written informed consent and assent process 2. Is age ≥ 12 years and ≤ 17 years on Study Day 0 3. Agrees to stay in contact with the study site for the duration of the study, provide updated contact information 4. For female subjects: agrees to avoid pregnancy from 28 days prior to Study Day 0 and for the full duration of the study. 5. Has general good health, confirmed by medical history and physical examination 6. Had BCG vaccination at least 5 years ago documented through medical history or by presence of healed BCG scar 7. Tests QFT-GIT negative at screening, using the manufacturer's recommended threshold of 0.35 IU/mL
Exclusion criteria
1. Acute illness on Study Day 0 2. Oral temperature ≥37.5°C on Study Day 0 3. Clinically significant (and no more than Grade 1 on the Toxicity Scale) abnormal laboratory values from blood collected within 21 days 4. Evidence of clinically significant (and no more than Grade 1 on the Toxicity Scale) systemic or local disease on urinalysis 5. History or evidence of any clinically significant systemic disease, or any acute or chronic illness that might affect the safety, immunogenicity, or efficacy of study vaccine in the opinion of the investigator 6. History of treatment for active TB disease or latent Mtb infection 7. History or evidence, including chest X-ray, of active TB disease 8. Shared residence with an individual receiving anti-TB treatment, or known incompletely treated culture or smear positive TB 9. History of autoimmune disease or immunosuppression 10. Used immunosuppressive medication within 42 days before Study Day 0 11. Received immunoglobulin or blood products within 42 days before Study Day 0 12. Received any investigational drug therapy or investigational vaccine within 182 days before Study Day 0 13. Received investigational TB vaccine, other than BCG 14. Planned administration/administration of a licensed vaccine in the period starting 28 days before and ending 28 days after each dose of study vaccine 15. History or laboratory evidence of any past or present possible immunodeficiency state not limited to any lab indication of HIV-1 infection 16. History of allergic disease likely to be exacerbated by any component of the study vaccine 17. History of alcohol or drug abuse 18. All female subjects: currently pregnant or lactating/nursing; or positive urine pregnancy test during screening 19. Received a (TST) within 3 months (90 days) prior to Study Day 0. 20. Any current medical, psychiatric, occupational, substance abuse problems problems that in opinion of investigator will make unlikely for the subject to comply with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Profile of H4:IC31 and BCG Revaccination in HIV-uninfected, Remotely BCG Vaccinated Adolescents. | Study day 7 thru 6 months after last vaccination | Number of unsolicited and solicited adverse events recorded post vaccination. Unsolicited adverse events: 28 days post each vaccination Solicited adverse events: 7 days post each vaccination (with diary cards used for 7 days after each vaccination for Safety and Immunogenicity Cohort only) Solicited and unsolicited injection site reaction adverse events: BCG Group - 84 days post vaccination; H4:IC31/Placebo Groups - 28 days post each vaccination Serious adverse events, adverse events of special interest, and SUSARs: Entire study period, with a minimum of 6 months following the last dose of study vaccine |
| Number of Participants Testing Positive for Mtb at Day 84 | Study day 84 through 6 months post-conversion | Rates of conversion to Mtb-positive measured by QuantiFERON-TB Gold In-tube (QFT-GIT) assay. The primary evaluation of Mtb infection was 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. All participants with primary QFT-GIT conversion were followed for an additional 6 months post-conversion to ascertain the sustained QFT-GIT conversion and QFT-GIT reversion endpoints. Participants with an initial QFT-GIT conversion at Month 6 or 12 were asked to return for a final QFT-GIT evaluation and assessment for TB signs and symptoms at least 24 months after their initial vaccination. * H4:IC31 compared to placebo * BCG revaccination compared to placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rates of Sustained Conversion to Mtb-positive | 6 months after initial conversion | Rates of sustained conversion to Mtb-positive as measured by QFT-GIT assay. * H4:IC31 compared to placebo * BCG revaccination compared to placebo |
| Percentage of Participants With Immune Response to Vaccine in HIV-uninfected, Remotely BCG-vaccinated Adolescents: o H4:IC31 o BCG Revaccination | Study day 70 | A 13 color intracellular cytokine staining assay (ICS) was performed on peripheral blood mononuclear cells (PBMC) to assess CD4+ T cells that expressed 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 TB mycobacterial antigens Ag85B and TB10.4, and BCG antigens. Responders were IFN-gamma and/or IL-2 positive. An intracellular cytokine assay was performed on whole blood (WB) to measure the frequencies and patterns of CD4+ T cells expressing Th1 and Th17 cytokines following stimulation of whole blood with peptide pools representing the entire amino acid sequence of the TB mycobacterial antigens Ag85B and TB10.4, as well as viable BCG from the vaccine vial. Responders were IFN-gamma, IL-2, TNF, IL-17, and/or IL-22 positive. |
Countries
South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AERAS-404 (15 mcgH4/500 Nmol IC31) 2 doses on Study Days 0 and 56
AERAS-404: 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. | 330 |
| Bacillus Calmette-Guérin (BCG) 1 Dose on Study Day 0
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). | 330 |
| Placebo 2 Doses on Study Days 0 and 56
Placebo: Saline | 329 |
| Total | 989 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | participant refused to use contraception | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | AERAS-404 (15 mcgH4/500 Nmol IC31) | Bacillus Calmette-Guérin (BCG) |
|---|---|---|---|---|
| Age, Categorical <=18 years | 329 Participants | 989 Participants | 330 Participants | 330 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 14.3 years STANDARD_DEVIATION 1.54 | 14.2 years STANDARD_DEVIATION 1.5 | 14.1 years STANDARD_DEVIATION 1.47 | 14.2 years STANDARD_DEVIATION 1.49 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 329 Participants | 989 Participants | 330 Participants | 330 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 120 Participants | 366 Participants | 120 Participants | 126 Participants |
| Race (NIH/OMB) More than one race | 207 Participants | 615 Participants | 208 Participants | 200 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 5 Participants | 1 Participants | 3 Participants |
| Region of Enrollment South Africa | 329 Participants | 989 Participants | 330 Participants | 330 Participants |
| Sex: Female, Male Female | 169 Participants | 520 Participants | 189 Participants | 162 Participants |
| Sex: Female, Male Male | 160 Participants | 469 Participants | 141 Participants | 168 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 330 | 0 / 330 | 1 / 329 |
| other Total, other adverse events | 118 / 330 | 329 / 330 | 104 / 329 |
| serious Total, serious adverse events | 5 / 330 | 7 / 330 | 7 / 329 |
Outcome results
Primary
Number of Participants Testing Positive for Mtb at Day 84
Rates of conversion to Mtb-positive measured by QuantiFERON-TB Gold In-tube (QFT-GIT) assay. The primary evaluation of Mtb infection was 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. All participants with primary QFT-GIT conversion were followed for an additional 6 months post-conversion to ascertain the sustained QFT-GIT conversion and QFT-GIT reversion endpoints. Participants with an initial QFT-GIT conversion at Month 6 or 12 were asked to return for a final QFT-GIT evaluation and assessment for TB signs and symptoms at least 24 months after their initial vaccination. * H4:IC31 compared to placebo * BCG revaccination compared to placebo
Time frame: Study day 84 through 6 months post-conversion
Population: Intent-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AERAS-404 (15 mcgH4/500 Nmol IC31) | Number of Participants Testing Positive for Mtb at Day 84 | 44 participants |
| Bacillus Calmette-Guérin (BCG) | Number of Participants Testing Positive for Mtb at Day 84 | 41 participants |
| Placebo | Number of Participants Testing Positive for Mtb at Day 84 | 49 participants |
Primary
Safety Profile of H4:IC31 and BCG Revaccination in HIV-uninfected, Remotely BCG Vaccinated Adolescents.
Number of unsolicited and solicited adverse events recorded post vaccination. Unsolicited adverse events: 28 days post each vaccination Solicited adverse events: 7 days post each vaccination (with diary cards used for 7 days after each vaccination for Safety and Immunogenicity Cohort only) Solicited and unsolicited injection site reaction adverse events: BCG Group - 84 days post vaccination; H4:IC31/Placebo Groups - 28 days post each vaccination Serious adverse events, adverse events of special interest, and SUSARs: Entire study period, with a minimum of 6 months following the last dose of study vaccine
Time frame: Study day 7 thru 6 months after last vaccination
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AERAS-404 (15 mcgH4/500 Nmol IC31) | Safety Profile of H4:IC31 and BCG Revaccination in HIV-uninfected, Remotely BCG Vaccinated Adolescents. | 286 number of AEs |
| Bacillus Calmette-Guérin (BCG) | Safety Profile of H4:IC31 and BCG Revaccination in HIV-uninfected, Remotely BCG Vaccinated Adolescents. | 1257 number of AEs |
| Placebo | Safety Profile of H4:IC31 and BCG Revaccination in HIV-uninfected, Remotely BCG Vaccinated Adolescents. | 272 number of AEs |
Secondary
Percentage of Participants With Immune Response to Vaccine in HIV-uninfected, Remotely BCG-vaccinated Adolescents: o H4:IC31 o BCG Revaccination
A 13 color intracellular cytokine staining assay (ICS) was performed on peripheral blood mononuclear cells (PBMC) to assess CD4+ T cells that expressed 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 TB mycobacterial antigens Ag85B and TB10.4, and BCG antigens. Responders were IFN-gamma and/or IL-2 positive. An intracellular cytokine assay was performed on whole blood (WB) to measure the frequencies and patterns of CD4+ T cells expressing Th1 and Th17 cytokines following stimulation of whole blood with peptide pools representing the entire amino acid sequence of the TB mycobacterial antigens Ag85B and TB10.4, as well as viable BCG from the vaccine vial. Responders were IFN-gamma, IL-2, TNF, IL-17, and/or IL-22 positive.
Time frame: Study day 70
Population: Modified ITT analysis set: Safety and immunogenicity cohort
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AERAS-404 (15 mcgH4/500 Nmol IC31) | Percentage of Participants With Immune Response to Vaccine in HIV-uninfected, Remotely BCG-vaccinated Adolescents: o H4:IC31 o BCG Revaccination | PBMC ICS: Percent of responders on day 70 | 81.8 percentage of participants |
| AERAS-404 (15 mcgH4/500 Nmol IC31) | Percentage of Participants With Immune Response to Vaccine in HIV-uninfected, Remotely BCG-vaccinated Adolescents: o H4:IC31 o BCG Revaccination | WB ICS: Percent responders on day 70 | 12.5 percentage of participants |
| Bacillus Calmette-Guérin (BCG) | Percentage of Participants With Immune Response to Vaccine in HIV-uninfected, Remotely BCG-vaccinated Adolescents: o H4:IC31 o BCG Revaccination | PBMC ICS: Percent of responders on day 70 | 16.0 percentage of participants |
| Bacillus Calmette-Guérin (BCG) | Percentage of Participants With Immune Response to Vaccine in HIV-uninfected, Remotely BCG-vaccinated Adolescents: o H4:IC31 o BCG Revaccination | WB ICS: Percent responders on day 70 | 8.0 percentage of participants |
| Placebo | Percentage of Participants With Immune Response to Vaccine in HIV-uninfected, Remotely BCG-vaccinated Adolescents: o H4:IC31 o BCG Revaccination | PBMC ICS: Percent of responders on day 70 | 12.0 percentage of participants |
| Placebo | Percentage of Participants With Immune Response to Vaccine in HIV-uninfected, Remotely BCG-vaccinated Adolescents: o H4:IC31 o BCG Revaccination | WB ICS: Percent responders on day 70 | 8.3 percentage of participants |
Secondary
Rates of Sustained Conversion to Mtb-positive
Rates of sustained conversion to Mtb-positive as measured by QFT-GIT assay. * H4:IC31 compared to placebo * BCG revaccination compared to placebo
Time frame: 6 months after initial conversion
Population: Modified Intent-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AERAS-404 (15 mcgH4/500 Nmol IC31) | Rates of Sustained Conversion to Mtb-positive | 25 participants |
| Bacillus Calmette-Guérin (BCG) | Rates of Sustained Conversion to Mtb-positive | 21 participants |
| Placebo | Rates of Sustained Conversion to Mtb-positive | 36 participants |