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

NCT02075203 | Completed Phase 2 Results DMC

• 1 other identifier: C-040-404
• Study Type: interventional
• Target: 989
• Locations: 1 country
• Sites: 2

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

Conditions

Tuberculosis

Keywords

BCG Vaccinated

Outcome Measures

Primary Outcomes (2)

• 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

  Study day 7 thru 6 months after last vaccination

• 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

  Study day 84 through 6 months post-conversion

Secondary Outcomes (2)

• Rates of Sustained Conversion to Mtb-positive

  6 months after initial conversion

• Percentage of Participants With Immune Response to Vaccine in HIV-uninfected, Remotely BCG-vaccinated Adolescents: o H4:IC31 o BCG Revaccination

  Study day 70

Study Arms (3)

AERAS-404 (15 mcgH4/500 nmol IC31)

EXPERIMENTAL

2 doses on Study Days 0 and 56

Biological: AERAS-404

Bacillus Calmette-Guérin (BCG)

ACTIVE COMPARATOR

1 Dose on Study Day 0

Biological: Bacillus Calmette-Guérin (BCG)

Placebo

PLACEBO COMPARATOR

2 Doses on Study Days 0 and 56

Drug: Placebo

Interventions

AERAS-404 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.

Also known as: H4, H4:IC31

AERAS-404 (15 mcgH4/500 nmol IC31)

Placebo DRUG

Saline

Also known as: 0.9% Saline

Placebo

Bacillus Calmette-Guérin (BCG) 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).

Also known as: BCG, BCG SSI

Bacillus Calmette-Guérin (BCG)

Eligibility Criteria

• Age: 12 Years - 17 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• Has completed the written informed consent and assent process
• Is age ≥ 12 years and ≤ 17 years on Study Day 0
• Agrees to stay in contact with the study site for the duration of the study, provide updated contact information
• For female subjects: agrees to avoid pregnancy from 28 days prior to Study Day 0 and for the full duration of the study.
• Has general good health, confirmed by medical history and physical examination
• Had BCG vaccination at least 5 years ago documented through medical history or by presence of healed BCG scar
• Tests QFT-GIT negative at screening, using the manufacturer's recommended threshold of 0.35 IU/mL

You may not qualify if:

• Acute illness on Study Day 0
• Oral temperature ≥37.5°C on Study Day 0
• Clinically significant (and no more than Grade 1 on the Toxicity Scale) abnormal laboratory values from blood collected within 21 days
• Evidence of clinically significant (and no more than Grade 1 on the Toxicity Scale) systemic or local disease on urinalysis
• 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
• History of treatment for active TB disease or latent Mtb infection
• History or evidence, including chest X-ray, of active TB disease
• Shared residence with an individual receiving anti-TB treatment, or known incompletely treated culture or smear positive TB
• History of autoimmune disease or immunosuppression
• Used immunosuppressive medication within 42 days before Study Day 0
• Received immunoglobulin or blood products within 42 days before Study Day 0
• Received any investigational drug therapy or investigational vaccine within 182 days before Study Day 0
• Received investigational TB vaccine, other than BCG
• Planned administration/administration of a licensed vaccine in the period starting 28 days before and ending 28 days after each dose of study vaccine
• History or laboratory evidence of any past or present possible immunodeficiency state not limited to any lab indication of HIV-1 infection

Sponsors & Collaborators

• Aeras: lead
• Sanofi Pasteur, a Sanofi Company: collaborator

Study Sites (2)

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

Cape Town, Western Cape, 6850, South Africa

Location

Desmond Tutu HIV Foundation (DTHF)

Nyanga, South Africa

Location

Related Publications (2)

• 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.

  PMID: 29996082 RESULT

• 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.

  PMID: 26048780 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

Saline Solution

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

• Title: Dr. Mark Hatherill
• Organization: SATVI

mark.hatherill@uct.ac.za

+27214066145

Study Officials

• Mark Hatherill, MD

  The South African Tuberculosis Vaccine Initiative(SATVI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 17, 2014
• First Posted: March 3, 2014
• Study Start: February 1, 2014
• Primary Completion: August 28, 2017
• Study Completion: October 6, 2017
• Last Updated: September 4, 2019
• Results First Posted: July 29, 2019

Record last verified: 2019-05

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (2)