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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)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02075203
First Posted: March 3, 2014
Last Update Posted: October 9, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Sanofi Pasteur, a Sanofi Company
Information provided by (Responsible Party):
Aeras
  Purpose
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

Condition Intervention Phase
Tuberculosis Biological: AERAS-404 Drug: Placebo Biological: Bacillus Calmette-Guérin (BCG) Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Aeras:

Primary Outcome Measures:
  • 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. ]

Secondary Outcome Measures:
  • 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.


Estimated Enrollment: 990
Study Start Date: February 2014
Study Completion Date: October 6, 2017
Primary Completion Date: August 28, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AERAS-404 (15 mcgH4/500 nmol IC31)
2 doses on Study Days 0 and 56
Biological: 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.
Other Names:
  • H4
  • H4:IC31
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).
Other Names:
  • BCG
  • BCG SSI
Placebo Comparator: Placebo
2 Doses on Study Days 0 and 56
Drug: Placebo
Tris buffered saline (10mM Tris,pH 7.4, 150NM sodium chloride)
Other Name: Tris buffered saline

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   12 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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. Has body mass index (BMI) for age and sex between the 5th and 95th centiles by Centers for Disease Control nomogram
  7. Had BCG vaccination at least 5 years ago documented through medical history or by presence of healed BCG scar
  8. 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. History or laboratory evidence of any past or present possible immunodeficiency state not limited to any lab indication of HIV-1 infection
  15. History of allergic disease likely to be exacerbated by any component of the study vaccine
  16. History of alcohol or drug abuse
  17. All female subjects: currently pregnant or lactating/nursing; or positive urine pregnancy test during screening
  18. Received a (TST) within 3 months (90 days) prior to Study Day 0.
  19. 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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02075203


Locations
South Africa
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
Sponsors and Collaborators
Aeras
Sanofi Pasteur, a Sanofi Company
Investigators
Study Director: Robert Hopkins, MD Aeras
Principal Investigator: Mark Hatherill The South African Tuberculosis Vaccine Initiative(SATVI)
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Aeras
ClinicalTrials.gov Identifier: NCT02075203     History of Changes
Other Study ID Numbers: C-040-404
First Submitted: February 17, 2014
First Posted: March 3, 2014
Last Update Posted: October 9, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Aeras:
BCG Vaccinated

Additional relevant MeSH terms:
Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
BCG Vaccine
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs