TuberculosisPhase 1NCT02378207
Safety and Immunogenicity Study of BCG, H4:IC31, and H56:IC31 Revaccination in Healthy Adolescents
A Phase 1 study testing H4:IC31, H56:IC31 and BCG in people with Tuberculosis, run by Aeras at 1 site in South Africa.
Trial summary
The aims of the phase 1b trial described here are to facilitate identification of assays and immune responses that could then be evaluated as correlates of risk and correlates of protection in efficacy studies and ultimately to provide leads for biomarkers of protection against tuberculosis. Read more about this study
- Who is it for?
- Ages 12 to 17 yearsHealthy volunteers can take part
- Conditions the study is for
- Tuberculosis
- What is being tested?
- H4:IC31, H56:IC31 and BCG
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 84 participants
- Where
- 1 siteSouth Africa
- Study dates
- May 2015to 9 Dec 2016
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 17 years
- All sexes
- Healthy volunteers accepted
- Child
Who may be able to join
- Age of 12 to ≤ 17 years at enrollment
- Minimum weight ≥ 40 kg
- Previous BCG vaccination at least 5 years ago documented by scarification or medical card
- No evidence of active TB disease, as determined by history, physical examination and, if deemed appropriate, sputum investigation and / or chest x-ray.
- Negative QFT-GIT test at screening, using the manufacturer's recommended threshold of 0.35 IU/mL
- Assessed by the clinic staff as being at low risk for HIV infection
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- Hemoglobin ≥ 11.7 g/dL for females, ≥ 12.5 g/dL for males
- Negative HIV-1 and -2 blood test
- Agree to consistently use effective contraception for sexual activity that could lead to pregnancy from at least 20 days prior to enrollment through the last required protocol clinic visit.
- (additional minor criteria not added due to space constraints)
Who cannot join
- Blood products received within 120 days before first vaccination
- Investigational research agents received within 182 days before first vaccination
- Intent to participate in another study of an investigational research agent during the planned duration of the HVTN 602 / AERAS A-042 study
- Pregnant or breastfeeding
- History of alcohol or drug abuse
- A significant contact with active TB disease: for example, shared residency with an individual receiving anti-TB treatment, or with an individual known to have incompletely treated culture or smear positive TB
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- TB prophylaxis within 90 days prior to enrollment
- History of treatment for active TB disease or latent Mtb infection
- Positive and indeterminate QFT-GIT result
- Received a tuberculin skin test (TST) within 90 days prior to enrollment
- Vaccines and other Injections
- Immunosuppressive medications received within 168 days before first vaccination.
- Serious adverse reactions to vaccines including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain.
- Immunoglobulin received within 60 days before first vaccination
- Autoimmune disease Not excluded: mild, well-controlled psoriasis
- Clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health. Including but not limited to: Diabetes mellitus type 1 or type 2, Thyroidectomy, or Thyroid disease, Asthma, Asplenia, Bleeding disorders, malignancy, Seizure disorder, and Angioedema
- (additional minor criteria not added due to space constraints)
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Randomized, Placebo-controlled, Partially Blinded Phase 1b Clinical Trial to Evaluate the Safety and Immunogenicity of BCG Revaccination, H4:IC31, and H56:IC31 in Healthy, HIV-1-Uninfected Adolescent Participants
The aims of the phase 1b trial described here are to facilitate identification of assays and immune responses that could then be evaluated as correlates of risk and correlates of protection in efficacy studies and ultimately to provide leads for biomarkers of protection against tuberculosis. This study will complement one ongoing study (NCT02075203) evaluating the prevention of M. Tuberculosis infection using H4:IC31 (also known as AERAS-404).
Read the detailed description
This study proposes to further evaluate the safety and immunogenicity of H4:IC31, H56:IC31, and BCG revaccination. The study will be conducted in previously BCG vaccinated healthy adolescents, and will entail a thorough immunogenicity evaluation of these regimens incorporating unbiased systems vaccinology approaches and novel assessments of baseline and elicited responses that may impact vaccine responses. A major goal for this study is to generate immunological data on a wide range of immune responses using a variety of approaches including validated assessments, unbiased strategies, and novel exploratory assays to increase the likelihood of detecting responses correlating with risk or protection in the prevention of infection study. Investigators contributing to the proposed study have participated in a correlates analysis for an HIV vaccine exhibiting modest efficacy in which 2 correlates of risk were identified.
An additional aim of this study is to explore factors affecting vaccine induced responses that may also impact efficacy. For example, it is hypothesized that exposure to environmental mycobacteria may alter protection provided by BCG vaccination. Reagents for evaluating levels of exposure to environmental mycobacteria are in development as part of a concurrent collaborative study. An exploratory objective for this trial is to apply these reagents to examine whether such exposures influence immune responses elicited by the study vaccine and regimens.
- Conditions
- Tuberculosis
- Being tested
- H4:IC31, H56:IC31, BCG, Control Sodium Chloride 0.9%
- Medical subject headings
- Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
H4:IC31Biological
H4 contains Mtb antigens Ag85B and TB10.4
H56:IC31Biological
H56 contains Mtb antigens ESAT-6, and Rv2660c
BCGBiological
Control Sodium Chloride 0.9%Biological
| Study group | Role | What they receive |
|---|---|---|
| Group 1 H4:IC31 | Experimental | 15 mcg H4/500 nmol IC31 administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56. Receives: Biological: H4:IC31 |
| Group 2 H56:IC31 | Experimental | 5 mcg H56/500 nmol IC31 administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56. Receives: Biological: H56:IC31 |
| Group 3 BCG (2-8 x 105 CFU) | Active comparator | Administered IM as 0.1 mL in either deltoid muscle at Day 0. Receives: Biological: BCG |
| Group 4 Control Sodium Chloride 0.9% | Placebo comparator | Administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56. Receives: Biological: Control Sodium Chloride 0.9% |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Adverse Events
The number of solicited and unsolicited adverse events (AEs), including serious adverse events (SAEs), recorded post-vaccination for all participants.
Measured: Up to 8 months
Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline
Flow cytometry was used to examine TB Mb-specific CD4+ and CD8+ T-cell responses using the ICS assay. The antigens used to stimulate cells in this assay included peptide pools for the vaccine-matched proteins (Ag85B, ESAT-6, Rv2660c, and TB 10.4) as well as complex TB antigens (TB whole cell lysate [TB WCL], and BCG Pasteur strain.
Measured: Days 70 and 168
Secondary outcomes (5)
Evaluate Humoral Responses Elicited by the Different Vaccine Regimens.
Vaccine-specific binding antibodies elicited by the vaccine regimens as determined by multiplex antibody assay and/or enzyme-linked immunosorbent assay (ELISA).
Measured: Up to day 168.
* Evaluate Immune Response From Vaccine Regimens by Measuring Early (Innate) Vaccine-induced Peripheral Blood Transcription Profiles; Determine Which Responses Are Associated With Antigen-specific Adaptive Responses * Evaluate Adaptive Immune Response.
- Changes in gene expression measured in longitudinally-collected blood samples relative to samples collected at baseline. The transcriptional profiles will be correlated with antigen-specific adaptive responses measured in Primary objective 2.
- Transcriptional analysis of antigen-stimulated peripheral blood mononuclear cells (PBMC) at 2 weeks post vaccination will be performed..
Measured: Up to day 168
Evaluate Changes in Innate Cells in Response to the Vaccine Regimens
Blood concentrations of innate immune cell populations including lymphocyte populations, dendritic cells, monocytes, and granulocytes before and after vaccination
Measured: Up to day 168
Measure Non-classical Major Histocompatibility Complex (MHC)-Restricted T-cell Vaccine-induced Responses, Such as to Mycobacterial Lipids (CD1-restricted) and Metabolites (MR1-restricted).
- Frequency of CD4+, CD8+, and CD4/CD8 double-negative T-cell responses restricted by CD1 (recognizing specific Mtb lipids) before and after BCG revaccination in Group 3 participants.
- Frequency of mucosal-associated invariant T-cells (MAIT) restricted by MR1 (recognizing vitamin B metabolites) before and after BCG revaccination in Group 3 participants
Measured: Up to day 168
Evaluate QFT-GIT and ESAT-6 Free IGRA Discordance and Conversion/Reversion Rate During the Course of the Trial.
- Magnitude and positivity of interferon (IFN)-γ release using QFT-GIT ELISA in QFT-GIT tests.
- Magnitude and positivity of IFN-γ release using QFT-GIT ELISA in ESAT-6 free IGRAs.
Measured: Up to day 168
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Mar 2015 (estimated)
- Study startMay 2015
- Primary completion31 Oct 2016
- Study completion9 Dec 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 84 participants (actual)
Sponsor and investigators
- Lead sponsor
- Aeras
- Sponsor type
- University, hospital or other
- Collaborators
- HIV Vaccine Trials Network, Sanofi Pasteur, a Sanofi Company, Statens Serum Institut
- Responsible party
- Sponsor
- Investigators
- Linda-Gail Bekker, MD, Study chair, Desmond Tutu HIV CentreJim Kublin, MD, Study chair, HVTN Core, FHCRC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02378207
- Sponsor's protocol ID
- HVTN 602 / AERAS A-042
- Status last verified
- Jan 2018
- First submitted
- 12 Feb 2015
- Last updated
- 18 Nov 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Bekker LG, Dintwe O, Fiore-Gartland A, Middelkoop K, Hutter J, Williams A, Randhawa AK, Ruhwald M, Kromann I, Andersen PL, DiazGranados CA, Rutkowski KT, Tait D, Miner MD, Andersen-Nissen E, De Rosa SC, Seaton KE, Tomaras GD, McElrath MJ, Ginsberg A, Kublin JG; HVTN 602/Aeras A-042 Protocol Team. A phase 1b randomized study of the safety and immunological responses to vaccination with H4:IC31, H56:IC31, and BCG revaccination in Mycobacterium tuberculosis-uninfected adolescents in Cape Town, South Africa. EClinicalMedicine. 2020 Mar 18;21:100313. doi: 10.1016/j.eclinm.2020.100313. eCollection 2020 Apr.
PubMed 32382714
Study at a glance
From the registry record, last updated by the sponsor on 18 Nov 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Placebo-controlled, Partially Blinded Phase 1b Clinical Trial to Evaluate the Safety and Immunogenicity of BCG Revaccination, H4:IC31, and H56:IC31 in Healthy, HIV-1-Uninfected Adolescent Participants
- ClinicalTrials.gov ID
- NCT02378207
- Acronym / sponsor ID
- HVTN 602 / AERAS A-042
- Conditions
- Tuberculosis
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 84 participants (actual)
- Lead sponsor
- AerasUniversity, hospital or other
- Collaborators
- HIV Vaccine Trials Network, Sanofi Pasteur, a Sanofi Company, Statens Serum Institut
- Study start
- May 2015
- Primary completion
- 31 Oct 2016 (actual)
- Study completion
- 9 Dec 2016 (actual)
- First posted
- 4 Mar 2015 (estimated)
- Results
- Posted 18 Nov 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aims of the phase 1b trial described here are to facilitate identification of assays and immune responses that could then be evaluated as correlates of risk and correlates of protection in efficacy studies and ultimately to provide leads for biomarkers of protection against tuberculosis. This study will complement one ongoing study (NCT02075203) evaluating the prevention of M. Tuberculosis infection using H4:IC31 (also known as AERAS-404).
Detailed description
This study proposes to further evaluate the safety and immunogenicity of H4:IC31, H56:IC31, and BCG revaccination. The study will be conducted in previously BCG vaccinated healthy adolescents, and will entail a thorough immunogenicity evaluation of these regimens incorporating unbiased systems vaccinology approaches and novel assessments of baseline and elicited responses that may impact vaccine responses. A major goal for this study is to generate immunological data on a wide range of immune responses using a variety of approaches including validated assessments, unbiased strategies, and novel exploratory assays to increase the likelihood of detecting responses correlating with risk or protection in the prevention of infection study. Investigators contributing to the proposed study have participated in a correlates analysis for an HIV vaccine exhibiting modest efficacy in which 2 correlates of risk were identified.
An additional aim of this study is to explore factors affecting vaccine induced responses that may also impact efficacy. For example, it is hypothesized that exposure to environmental mycobacteria may alter protection provided by BCG vaccination. Reagents for evaluating levels of exposure to environmental mycobacteria are in development as part of a concurrent collaborative study. An exploratory objective for this trial is to apply these reagents to examine whether such exposures influence immune responses elicited by the study vaccine and regimens.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Group 1 H4:IC31 | Experimental | Biological: H4:IC3115 mcg H4/500 nmol IC31 administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56. |
| Group 2 H56:IC31 | Experimental | Biological: H56:IC315 mcg H56/500 nmol IC31 administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56. |
| Group 3 BCG (2-8 x 105 CFU) | Active comparator | Biological: BCGAdministered IM as 0.1 mL in either deltoid muscle at Day 0. |
| Group 4 Control Sodium Chloride 0.9% | Placebo comparator | Biological: Control Sodium Chloride 0.9%Administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56. |
Who may qualify
- Ages
- 12 to 17 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
Key inclusion criteria (10 listed)
- Age of 12 to ≤ 17 years at enrollment
- Minimum weight ≥ 40 kg
- Previous BCG vaccination at least 5 years ago documented by scarification or medical card
- No evidence of active TB disease, as determined by history, physical examination and, if deemed appropriate, sputum investigation and / or chest x-ray.
- Negative QFT-GIT test at screening, using the manufacturer's recommended threshold of 0.35 IU/mL
Key exclusion criteria (17 listed)
- Blood products received within 120 days before first vaccination
- Investigational research agents received within 182 days before first vaccination
- Intent to participate in another study of an investigational research agent during the planned duration of the HVTN 602 / AERAS A-042 study
- Pregnant or breastfeeding
- History of alcohol or drug abuse
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| H4:IC31H4 contains Mtb antigens Ag85B and TB10.4 | Biological | Group 1 H4:IC31 |
| H56:IC31H56 contains Mtb antigens ESAT-6, and Rv2660c | Biological | Group 2 H56:IC31 |
| BCG | Biological | Group 3 BCG (2-8 x 105 CFU) |
| Control Sodium Chloride 0.9% | Biological | Group 4 Control Sodium Chloride 0.9% |
Primary outcome
Number of Participants With Adverse Events
Time frame: Up to 8 months
The number of solicited and unsolicited adverse events (AEs), including serious adverse events (SAEs), recorded post-vaccination for all participants.
Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline
Time frame: Days 70 and 168
Flow cytometry was used to examine TB Mb-specific CD4+ and CD8+ T-cell responses using the ICS assay. The antigens used to stimulate cells in this assay included peptide pools for the vaccine-matched proteins (Ag85B, ESAT-6, Rv2660c, and TB 10.4) as well as complex TB antigens (TB whole cell lysate [TB WCL], and BCG Pasteur strain.
5 secondary outcomes
Evaluate Humoral Responses Elicited by the Different Vaccine Regimens.
Time frame: Up to day 168.
* Evaluate Immune Response From Vaccine Regimens by Measuring Early (Innate) Vaccine-induced Peripheral Blood Transcription Profiles; Determine Which Responses Are Associated With Antigen-specific Adaptive Responses * Evaluate Adaptive Immune Response.
Time frame: Up to day 168
Evaluate Changes in Innate Cells in Response to the Vaccine Regimens
Time frame: Up to day 168
Measure Non-classical Major Histocompatibility Complex (MHC)-Restricted T-cell Vaccine-induced Responses, Such as to Mycobacterial Lipids (CD1-restricted) and Metabolites (MR1-restricted).
Time frame: Up to day 168
Evaluate QFT-GIT and ESAT-6 Free IGRA Discordance and Conversion/Reversion Rate During the Course of the Trial.
Time frame: Up to day 168
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Nov 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 32382714Bekker LG, Dintwe O, Fiore-Gartland A, Middelkoop K, Hutter J, Williams A, Randhawa AK, Ruhwald M, Kromann I, Andersen PL, DiazGranados CA, Rutkowski KT, Tait D, Miner MD, Andersen-Nissen E, De Rosa SC, Seaton KE, Tomaras GD, McElrath MJ, Ginsberg A, Kublin JG; HVTN 602/Aeras A-042 Protocol Team. A phase 1b randomized study of the safety and immunological responses to vaccination with H4:IC31, H56:IC31, and BCG revaccination in Mycobacterium tuberculosis-uninfected adolescents in Cape Town, South Africa. EClinicalMedicine. 2020 Mar 18;21:100313. doi: 10.1016/j.eclinm.2020.100313. eCollection 2020 Apr.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Linda-Gail Bekker, MD study chair
Desmond Tutu HIV Centre
Jim Kublin, MD study chair
HVTN Core, FHCRC
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing H4:IC31, H56:IC31 and BCG in people with Tuberculosis, run by Aeras at 1 site in South Africa.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Nov 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Nov 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Adverse Events (time frame: Up to 8 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02378207, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Nov 2019.