Trial Outcomes & Findings for Evaluation of Safety, Immunogenicity, and Prevention of TB With AERAS-404 and BCG Revaccination in Healthy Adolescents (NCT NCT02075203)

NCT ID: NCT02075203

Last Updated: 2019-09-04

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

989 participants

Primary outcome timeframe

Study day 7 thru 6 months after last vaccination

Results posted on

2019-09-04

Participant Flow

Participant milestones

Participant milestones
Measure	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.	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).	Placebo 2 Doses on Study Days 0 and 56 Placebo: Saline
Overall Study STARTED	330	330	329
Overall Study COMPLETED	327	330	328
Overall Study NOT COMPLETED	3	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	Placebo 2 Doses on Study Days 0 and 56 Placebo: Saline
Overall Study Withdrawal by Subject	1	1
Overall Study Adverse Event	1	0
Overall Study participant refused to use contraception	1	0

Baseline Characteristics

Evaluation of Safety, Immunogenicity, and Prevention of TB With AERAS-404 and BCG Revaccination in Healthy Adolescents

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	AERAS-404 (15 mcgH4/500 Nmol IC31) n=330 Participants 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.	Bacillus Calmette-Guérin (BCG) n=330 Participants 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).	Placebo n=329 Participants 2 Doses on Study Days 0 and 56 Placebo: Saline	Total n=989 Participants Total of all reporting groups
Age, Categorical <=18 years	330 Participants n=5 Participants	330 Participants n=7 Participants	329 Participants n=5 Participants	989 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Continuous	14.1 years STANDARD_DEVIATION 1.47 • n=5 Participants	14.2 years STANDARD_DEVIATION 1.49 • n=7 Participants	14.3 years STANDARD_DEVIATION 1.54 • n=5 Participants	14.2 years STANDARD_DEVIATION 1.50 • n=4 Participants
Sex: Female, Male Female	189 Participants n=5 Participants	162 Participants n=7 Participants	169 Participants n=5 Participants	520 Participants n=4 Participants
Sex: Female, Male Male	141 Participants n=5 Participants	168 Participants n=7 Participants	160 Participants n=5 Participants	469 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	330 Participants n=5 Participants	330 Participants n=7 Participants	329 Participants n=5 Participants	989 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	120 Participants n=5 Participants	126 Participants n=7 Participants	120 Participants n=5 Participants	366 Participants n=4 Participants
Race (NIH/OMB) White	1 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants
Race (NIH/OMB) More than one race	208 Participants n=5 Participants	200 Participants n=7 Participants	207 Participants n=5 Participants	615 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment South Africa	330 Participants n=5 Participants	330 Participants n=7 Participants	329 Participants n=5 Participants	989 Participants n=4 Participants

PRIMARY outcome

Timeframe: Study day 7 thru 6 months after last vaccination

Outcome measures

Outcome measures
Measure	AERAS-404 (15 mcgH4/500 Nmol IC31) n=330 Participants 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.	Bacillus Calmette-Guérin (BCG) n=330 Participants 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).	Placebo n=329 Participants 2 Doses on Study Days 0 and 56 Placebo: Saline
Safety Profile of H4:IC31 and BCG Revaccination in HIV-uninfected, Remotely BCG Vaccinated Adolescents.	286 number of AEs	1257 number of AEs	272 number of AEs

PRIMARY outcome

Timeframe: Study day 84 through 6 months post-conversion

Population: Intent-to-Treat

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

Outcome measures

Outcome measures
Measure	AERAS-404 (15 mcgH4/500 Nmol IC31) n=308 Participants 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.	Bacillus Calmette-Guérin (BCG) n=312 Participants 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).	Placebo n=310 Participants 2 Doses on Study Days 0 and 56 Placebo: Saline
Number of Participants Testing Positive for Mtb at Day 84	44 participants	41 participants	49 participants

SECONDARY outcome

Timeframe: 6 months after initial conversion

Population: Modified Intent-to-Treat

Rates of sustained conversion to Mtb-positive as measured by QFT-GIT assay. * H4:IC31 compared to placebo * BCG revaccination compared to placebo

Outcome measures

Outcome measures
Measure	AERAS-404 (15 mcgH4/500 Nmol IC31) n=308 Participants 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.	Bacillus Calmette-Guérin (BCG) n=312 Participants 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).	Placebo n=310 Participants 2 Doses on Study Days 0 and 56 Placebo: Saline
Rates of Sustained Conversion to Mtb-positive	25 participants	21 participants	36 participants

SECONDARY outcome

Timeframe: Study day 70

Population: Modified ITT analysis set: Safety and immunogenicity cohort

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.

Outcome measures

Outcome measures
Measure	AERAS-404 (15 mcgH4/500 Nmol IC31) n=28 Participants 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.	Bacillus Calmette-Guérin (BCG) n=28 Participants 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).	Placebo n=27 Participants 2 Doses on Study Days 0 and 56 Placebo: Saline
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	16.0 percentage of participants	12.0 percentage of participants
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	8.0 percentage of participants	8.3 percentage of participants

Adverse Events

AERAS-404 (15 mcgH4/500 Nmol IC31)

Serious events: 5 serious events

Other events: 118 other events

Deaths: 0 deaths

Bacillus Calmette-Guerin (BCG)

Serious events: 7 serious events

Other events: 329 other events

Deaths: 0 deaths

Placebo

Serious events: 7 serious events

Other events: 104 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Dr. Mark Hatherill

SATVI

Phone: +27214066145

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place