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

NCT ID: NCT02075203

Last Updated: 2019-09-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 989 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-02-28
• Study Completion Date: 2017-10-06

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.

Conditions

Tuberculosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

AERAS-404 (15 mcgH4/500 nmol IC31)

2 doses on Study Days 0 and 56

Group Type: EXPERIMENTAL

AERAS-404

Intervention Type: BIOLOGICAL

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

Group Type: ACTIVE_COMPARATOR

Bacillus Calmette-Guérin (BCG)

Intervention Type: BIOLOGICAL

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Saline

Interventions

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.

Intervention Type: BIOLOGICAL

Placebo

Saline

Intervention Type: DRUG

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).

Intervention Type: BIOLOGICAL

Other Intervention Names

H4; H4:IC31; 0.9% Saline; BCG; BCG SSI

Eligibility 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. 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

• Minimum Eligible Age: 12 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Sanofi Pasteur, a Sanofi Company

INDUSTRY

Sponsor Role: collaborator

Aeras

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mark Hatherill, MD

Role: PRINCIPAL_INVESTIGATOR

The South African Tuberculosis Vaccine Initiative(SATVI)

Locations

South African Tuberculosis Vaccine Initiative , Project Office, Brewelskloof Hospital , Harlem Street, Worcester

Cape Town, Western Cape, South Africa

Desmond Tutu HIV Foundation (DTHF)

Nyanga, , South Africa

Countries

South Africa

References

Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F, Bilek N, Mabwe S, Makhethe L, Erasmus M, Toefy A, Mulenga H, Hanekom WA, Self SG, Bekker LG, Ryall R, Gurunathan S, DiazGranados CA, Andersen P, Kromann I, Evans T, Ellis RD, Landry B, Hokey DA, Hopkins R, Ginsberg AM, Scriba TJ, Hatherill M; C-040-404 Study Team. Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination. N Engl J Med. 2018 Jul 12;379(2):138-149. doi: 10.1056/NEJMoa1714021.

Reference Type: RESULT

PMID: 29996082 (View on PubMed)

Geldenhuys H, Mearns H, Miles DJ, Tameris M, Hokey D, Shi Z, Bennett S, Andersen P, Kromann I, Hoff ST, Hanekom WA, Mahomed H, Hatherill M, Scriba TJ; H4:IC31 Trial Study Group; van Rooyen M, Bruce McClain J, Ryall R, de Bruyn G; H4:IC31 Trial Study Groupa. The tuberculosis vaccine H4:IC31 is safe and induces a persistent polyfunctional CD4 T cell response in South African adults: A randomized controlled trial. Vaccine. 2015 Jul 9;33(30):3592-9. doi: 10.1016/j.vaccine.2015.05.036. Epub 2015 Jun 3.

Reference Type: DERIVED

PMID: 26048780 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

C-040-404

Identifier Type: -

Identifier Source: org_study_id