Phase 1/II, Safety and Immunogenicity Study of AERAS-404 in BCG-Primed Infants (C-015-404)

Phase 1/II, Safety and Immunogenicity Study of a Recombinant Protein Tuberculosis Vaccine (AERAS-404) in BCG-Primed Infants

Phase I/II, randomized, double-blind, placebo-controlled, safety, immunogenicity and dose-range finding study of AERAS-404 Tuberculosis (TB) vaccine administered intramuscularly in Bacille Calmette-Guerin (BCG) primed infants.

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Biological: AERAS-404; Biological: Placebo

Detailed Description

This is a Phase I/II, randomized, double-blind, placebo-controlled, safety, immunogenicity and dose-range finding study in HIV-uninfected, HIV-unexposed, BCG-primed infants. The study vaccine AERAS-404 or placebo will be administered without concomitant EPI vaccines (Cohorts 1 to 5, N = 159 subjects) and with concomitant EPI vaccines (Cohort 6, N = 70 subjects). Study vaccine or placebo will be administered as a single dose (injection) at Study Day 0 ( ≥168 to ≤ 196 days of age, Cohorts 1 and 2), a 2-dose schedule at Study Day 0 (≥ 168 to ≤ 189 days of age) and Study Day 28 (Cohorts 3A and 3B) or a 3-dose schedule at Study Day 0 (≥ 84 to ≤ 98 days of age), Study Day 42 and Study Day 98 (Cohorts 4 and 5). Subjects in Cohort 6 will receive the study vaccine or placebo at Study Day 0 (≥ 64 to ≤ 83 days of age), Study Day 28 (≥ 91 to ≤ 105 days of age), and Study Day 210 (≥ 273 to ≤ 287 days of age). A cohort will enroll once safety in the previous cohort has been established. AERAS-404 is an investigational vaccine manufactured by Sanofi Pasteur (SP) and Statens Serum Institute (SSI).

• Study Type: Interventional
• Enrollment (Actual): 243
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• South Africa
  • Worcester, South Africa
    • South African TB Vaccine Initiative (SATVI)
  • Guateng
    • Johannesburg, Guateng, South Africa, 2091
      • PHRU, Chris Hani Baragwanath Hospital
  • Hillbrow
    • Johannesburg, Hillbrow, South Africa, 2001
      • Shandukani Research
  • Tygerberg
    • Cape Town, Tygerberg, South Africa, 7505
      • KID-CRU, Tygerberg Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months to 6 months (CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

INCLUSION CRITERIA

1. Age at time of entry:

   Cohorts 1 to 6

   • Cohorts 1 and 2: ≥ 168 to ≤ 196 days
   • Cohorts 3A and 3B: ≥ 168 to ≤ 189 days
   • Cohorts 4 and 5: ≥ 84 to ≤ 98 days (≥ 2 weeks after receipt of EPI vaccine doses at 10 weeks of age)
   • Cohort 6 - coincident with EPI vaccine doses at 10 weeks of age (≥ 64 to ≤ 83 days of age)
2. Source documentation of birth weight ≥ 2.5 kg.
3. Documented BCG vaccination within 72 hours of birth.
4. Documented receipt of all age-appropriate EPI vaccines, except Rotavirus, for Cohorts 4 to 6 (see Appendix II).
5. Source documentation of a negative HIV status in the mother, from any time during pregnancy with this child through randomization.
6. Documentation of infant HIV negative exposure or infection status with negative HIV ELISA and HIV DNA PCR tests.
7. Parent or legal guardian able and willing to provide signed informed consent.
8. Participant/parent/legal guardian able to attend all scheduled visits and to comply with all trial procedures.

EXCLUSION CRITERIA

1. History of TB exposure in household or non-household contact.
2. History/Evidence of TB disease or infection.
3. Quantiferon positive.
4. Prior TST test.
5. Any one of Anemia, Neutropenia, Thrombocytopenia, SGPT (ALT), SGOT (AST) or Creatinine ≥ Grade 2
6. Receipt of a live vaccine within 28 days prior to randomization.
7. Receipt or planned receipt of any investigational vaccine.
8. Known or suspected congenital immunodeficiency.
9. Receipt of immunosuppressive therapy or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months).
10. Known or suspected autoimmune disease
11. Hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to a vaccine containing any of the same substances as the vaccine used in the trial.
12. Participation in another clinical trial for an investigational product (IP).
13. Bleeding disorder or receipt of anticoagulants in the 3 weeks preceding randomization, contraindicating IM vaccination.
14. Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere with trial conduct or completion.

15. Febrile illness (temperature ≥ 100.4°F [≥ 38.0°C]) within 24 hours prior to randomization.

    Note: A subject may enroll after recovery from febrile illness if the subject is still within the age window.

16. Systemic antibiotic use within 48 hours prior to randomization.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort 1 Aeras404 (5ug H4/100nmol IC31) or Placebo; 1 Dose; Subject ≥ 168 to ≤ 196 days of age	Biological: AERAS-404; AERAS-404 has two components: the H4 antigen and the IC31 adjuvant. The reconstitution of the vaccine components, H4 antigen (manufactured at SP) and IC31 adjuvant (supplied by SSI), will take place at the clinical research site (CRS) prior to injection.; Other Names: H4; Biological: Placebo; Tris buffered saline (10mM Tris, pH 7.4, 150nm sodium chloride).; Other Names: Tris buffered saline
EXPERIMENTAL: Cohort 2 AERAS-404 (5ug H4/500nmol IC31) or Placebo; 1 Dose; Subject ≥ 168 to ≤ 196 days of age	Biological: AERAS-404; AERAS-404 has two components: the H4 antigen and the IC31 adjuvant. The reconstitution of the vaccine components, H4 antigen (manufactured at SP) and IC31 adjuvant (supplied by SSI), will take place at the clinical research site (CRS) prior to injection.; Other Names: H4; Biological: Placebo; Tris buffered saline (10mM Tris, pH 7.4, 150nm sodium chloride).; Other Names: Tris buffered saline
EXPERIMENTAL: Cohort 3A AERAS-404 (5ug H4/500nmol IC31) or Placebo; 2 Doses; Subject ≥ 168 to ≤ 189 days of age	Biological: AERAS-404; AERAS-404 has two components: the H4 antigen and the IC31 adjuvant. The reconstitution of the vaccine components, H4 antigen (manufactured at SP) and IC31 adjuvant (supplied by SSI), will take place at the clinical research site (CRS) prior to injection.; Other Names: H4; Biological: Placebo; Tris buffered saline (10mM Tris, pH 7.4, 150nm sodium chloride).; Other Names: Tris buffered saline
EXPERIMENTAL: Cohort 3B AERAS-404 (15ug H4/500nmol IC31) or Placebo; 2 Doses; Subject ≥ 168 to ≤ 189 days of age	Biological: AERAS-404; AERAS-404 has two components: the H4 antigen and the IC31 adjuvant. The reconstitution of the vaccine components, H4 antigen (manufactured at SP) and IC31 adjuvant (supplied by SSI), will take place at the clinical research site (CRS) prior to injection.; Other Names: H4; Biological: Placebo; Tris buffered saline (10mM Tris, pH 7.4, 150nm sodium chloride).; Other Names: Tris buffered saline
EXPERIMENTAL: Cohort 4 AERAS-404 (15ug H4/500nmol IC31) or Placebo; 3 Doses; Subject ≥ 84 to ≤ 98 days of age	Biological: AERAS-404; AERAS-404 has two components: the H4 antigen and the IC31 adjuvant. The reconstitution of the vaccine components, H4 antigen (manufactured at SP) and IC31 adjuvant (supplied by SSI), will take place at the clinical research site (CRS) prior to injection.; Other Names: H4; Biological: Placebo; Tris buffered saline (10mM Tris, pH 7.4, 150nm sodium chloride).; Other Names: Tris buffered saline
EXPERIMENTAL: Cohort 5 AERAS-404 (50ug H4/500nmol IC31) or Placebo; 3 Doses; Subject ≥ 84 to ≤ 98 days of age	Biological: AERAS-404; AERAS-404 has two components: the H4 antigen and the IC31 adjuvant. The reconstitution of the vaccine components, H4 antigen (manufactured at SP) and IC31 adjuvant (supplied by SSI), will take place at the clinical research site (CRS) prior to injection.; Other Names: H4; Biological: Placebo; Tris buffered saline (10mM Tris, pH 7.4, 150nm sodium chloride).; Other Names: Tris buffered saline
EXPERIMENTAL: Cohort 6 AERAS-404 (dose level pending) or Placebo; 3 Doses; Subject ≥ 64 to ≤ 83 days of age	Biological: AERAS-404; AERAS-404 has two components: the H4 antigen and the IC31 adjuvant. The reconstitution of the vaccine components, H4 antigen (manufactured at SP) and IC31 adjuvant (supplied by SSI), will take place at the clinical research site (CRS) prior to injection.; Other Names: H4; Biological: Placebo; Tris buffered saline (10mM Tris, pH 7.4, 150nm sodium chloride).; Other Names: Tris buffered saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Investigate the safety of AERAS-404 in HIV-uninfected, HIV-unexposed, BCG-primed infants.	Adverse Events and Serious Adverse Events (SAE) will be collected on subjects throughout their participation in the study. Solicited adverse events are captured 28 days post each vaccination. Evaluation of the safety profile of AERAS-404 will be performed using data from all subjects who received at least one dose and has 7 days of safety data, and will be summarized by cohort and treatment group. The number (percentage) of subjects with any adverse event (including solicited, unsolicited, and serious adverse events) will be summarized by Medical Dictionary for Regulatory Activities (MedDRA) system organ class and Preferred Term. Additional summaries will present the number (percentage) of subjects with any adverse events by severity and by relationship to study vaccine; parameters evaluable by the Aeras 404 Pediatric Toxicity Table provided in the protocol, will be summarized by severity corresponding to Toxicity Grade, as appropriate.	Subjects will be followed for up to 1 year and 4 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Investigate the safety of a 3-dose AERAS-404 regimen in HIV-uninfected, HIV-unexposed, BCG-primed infants	The number and percentage of subjects who are enrolled into the three-dose regimen (Cohorts 4-6) with solicited and unsolicited AEs (including serious adverse events [SAEs], local and systemic reactions, and clinical laboratory values or vital sign values recorded as newly abnormal following study vaccination) recorded post-vaccination will be summarized to address the secondary safety objective of the study. Subjects in Cohorts 4 and 5 will be followed for : 1 year and 3 months, Cohort 6: 1 year 4 months and Solicited adverse events are captured 28 days post each vaccination.	Subjects will be followed for up to 1 year and 4 months.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the immunogenicity of a 3-dose AERAS-404 regimen in HIV-uninfected, HIV-unexposed, BCG-primed infants.	T-cell response, as measured by Intracellular Cytokine Staining (ICS) following stimulation with peptide pools spanning the vaccine antigens, will be used to assess immunogenicity.	Subjects will be followed for up to 1 year and 4 months.
Select an appropriate dose regimen for AERAS-404 in HIV-uninfected, HIV-unexposed, BCG-primed infants.	Safety and immunogenicity analyses will be reviewed for the selection of the appropriate dose regimen	After all subjects in Cohorts 4 and 5 have completed Study Day 126, the safety and immunogenicity data from these Cohorts will be evaluated. The data will inform the decision on the study vaccine dose for Cohort 6.
Explore interactions between AERAS-404 and EPI vaccines.	Antibody concentration levels at 12 months of age for all Cohorts, and in addition at 28 days post second study vaccine dose (Study Day 56) for Cohort 6 will be presented. Summaries will include antibody titers to Tetanus toxoid vaccine (tetanus; given at 6, 10, 14 weeks of age), and Haemophilus influenza B conjugate vaccine (given at 6, 10, 14 weeks of age). Responses to other EPI vaccines may also be assessed.	Antibody concentration blood samples taken when subjects reach 12 months of age for all Cohorts and in addition, 28 post second study vaccine dose (Study Day 56) for subjects in Cohort 6 only.
Assess the immunogenicity of a 2-dose AERAS-404 regimen in HIV-uninfected, HIV-unexposed, BCG-primed infants.		Subjects will have Immunology samples taken at multiple time points for up to 1 year and 4 months.

Collaborators and Investigators

• Sponsor: Aeras
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Sanofi Pasteur, a Sanofi Company; Statens Serum Institut; International Maternal Pediatric Adolescent AIDS Clinical Trials Group
• Investigators: Study Director: Ann Ginsberg, MD, PhD, Aeras; Principal Investigator: Avy Violari, MD, Perinatal HIV Research Unit

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 1, 2013
• Primary Completion (ACTUAL): December 22, 2017
• Study Completion (ACTUAL): December 22, 2017

Study Registration Dates

• First Submitted: May 21, 2013
• First Submitted That Met QC Criteria: May 22, 2013
• First Posted (ESTIMATE): May 24, 2013

Study Record Updates

• Last Update Posted (ACTUAL): April 9, 2018
• Last Update Submitted That Met QC Criteria: April 6, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: HIV Negative; BCG Vaccinated
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: C-015-404/ IMPAACT P1113; U01AI068632 (U.S. NIH Grant/Contract); C-015-404 (OTHER: Aeras)