A Phase I Randomized Placebo-Controlled, Double-Blind Study to Evaluate Safety and Immunogenicity of AERAS-404 Administered as Different Amounts of Antigen and Adjuvant Combinations in HIV-Negative BCG-Vaccinated Adults Without Evidence of Tuberculosis Infection

Study Overview
=================
Brief Summary
-----------------
Phase I, randomized, double blinded, Placebo-controlled, immunogenicity and dose-range finding study of AERAS-404 in Bacille Calmette-Guerin (BCG) healthy adult male and sterile females.

Detailed Description
-----------------
This ia a Phase I, randomized, placebo-controlled, double-blind study in three groups of healthy adult males or sterile females who are BCG-vaccinated, HIV-negative, and have no evidence of tuberculosis infection. Sixty-four subjects assigned to one of eight treatment groups to receive one of four different antigen/adjuvant combinations of study vaccine, or placebo control. Within each study group, subjects will be randomized to receive either a single-dose antigen/adjuvant regimen of study vaccine (vaccination with study vaccine on Study Day 0 followed by vaccination with placebo control on Study Day 56) or a two-dose antigen/adjuvant regimen of study vaccine (vaccination with study vaccine on Study Days 0 and 56). All subjects will be followed for safety and immunogenicity evaluations for 182 days. The sample sizes specified for each study group were selected because they are judged to be adequate for preliminary safety and immunogenicity evaluations for a Phase I study rather than for statistical reasons. If no SAE are observed among 56 subjects receiving active study vaccine, an approximation to the upper 95% confidence bound on the rate of SAE occurrence would be 5.4%.

Official Title
-----------------
A Phase I Randomized Placebo-Controlled, Double-Blind Study to Evaluate Safety and Immunogenicity of AERAS-404 Administered as Different Amounts of Antigen and Adjuvant Combinations in HIV-Negative BCG-Vaccinated Adults Without Evidence of Tuberculosis Infection

Conditions
-----------------
Tuberculosis

Intervention / Treatment
-----------------
* Biological: AERAS-404
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female Age 18 through 50 years on Study Day 0 Completed wriiten Informed Consent BCG vaccination at least 5 years ago, General good health, confirmed by medical history (BMI) between 19 and 33 (kg/m2) Has ability to complete follow-up period of 182 days as required Females must be physically incapable of conception Avoiding elective surgery for the duration of the study Stay in contact with the investigative site for the duration of the study Complete simultaneous enrollment in Aeras Vaccine Development Registry protocol Exclusion Criteria: Acute illness on the day of randomization Oral temperature >=37.5 degree Celcius on the day of randomization Evidence of significant active infection Used immunosuppressive medication within 42 days before entry into the study Received immunoglobulin or blood products within 42 days before entry into the study Received any investigational drug therapy or investigational vaccine within 182 days Received inactivated influenza vaccine or inactivated tick-borne encephalitis vaccine within 14 days before entry into the study. Current chronic drug therapy including hormone replacement such as thyroxin, insulin, etc. History or laboratory evidence of any past, present or future possible immunodeficiency state which will include any laboratory indication of virus type 1 (HIV-1) infection History of allergic disease or reactions, including eczema. Previous medical history that may compromise safety of subject Evidence of new acute illness that may compromise safety of subject Evidence of chronic hepatitis Inability to discontinue daily medication except contraception History of alcohol or drug abuse within 2yrs Tobacco or cannabis smoking three Positive urine test for illicit drugs History or evidence of any systemic disease on physical examination History of active TB Shared residence within 1 year with an individual on anti-TB treatment All females: nursing Abnormal hemoglobin,hematocrit etc drawn within 36 hours prior to randomization Laboratory test evidence of Mtb infection History of positive tuberculin skin test within past 10 years Received a tuberculin skin test within 3 years History of autoimmune disease

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AERAS-404(50mcg H4/0nmol IC31) or Placebo<br>1 dose | Biological: AERAS-404<br>* AERAS 404 (H4:IC31) contains a fusion protein of 2 mycobacterial antigens (Ag85B and TB 10.4) formulated in IC31 adjuvant.<br>* Other names: H4;Biological: Placebo<br>* Tris buffer saline consisting (10mM Tris and 169mM NaCI at pH7.4)<br>* Other names: Tris Buffered saline;|
| Experimental: AERAS404 (50mcgH4/100nmol IC31) or Placebo<br>1 dose | Biological: AERAS-404<br>* AERAS 404 (H4:IC31) contains a fusion protein of 2 mycobacterial antigens (Ag85B and TB 10.4) formulated in IC31 adjuvant.<br>* Other names: H4;Biological: Placebo<br>* Tris buffer saline consisting (10mM Tris and 169mM NaCI at pH7.4)<br>* Other names: Tris Buffered saline;|
| Experimental: AERAS404 (50mcgH4/0nmol IC31) or Placebo<br>2 dose | Biological: AERAS-404<br>* AERAS 404 (H4:IC31) contains a fusion protein of 2 mycobacterial antigens (Ag85B and TB 10.4) formulated in IC31 adjuvant.<br>* Other names: H4;Biological: Placebo<br>* Tris buffer saline consisting (10mM Tris and 169mM NaCI at pH7.4)<br>* Other names: Tris Buffered saline;|
| Experimental: AERAS404 (150mcgH4/0nmol IC31) or Placebo<br>1 dose | Biological: AERAS-404<br>* AERAS 404 (H4:IC31) contains a fusion protein of 2 mycobacterial antigens (Ag85B and TB 10.4) formulated in IC31 adjuvant.<br>* Other names: H4;Biological: Placebo<br>* Tris buffer saline consisting (10mM Tris and 169mM NaCI at pH7.4)<br>* Other names: Tris Buffered saline;|
| Experimental: AERAS404 (50mcgH4/5000nmol IC31) or Placebo<br>1 dose | Biological: AERAS-404<br>* AERAS 404 (H4:IC31) contains a fusion protein of 2 mycobacterial antigens (Ag85B and TB 10.4) formulated in IC31 adjuvant.<br>* Other names: H4;Biological: Placebo<br>* Tris buffer saline consisting (10mM Tris and 169mM NaCI at pH7.4)<br>* Other names: Tris Buffered saline;|
| Experimental: AERAS404 (50mcgH4/500nmol IC31) or Placebo<br>2 dose | Biological: AERAS-404<br>* AERAS 404 (H4:IC31) contains a fusion protein of 2 mycobacterial antigens (Ag85B and TB 10.4) formulated in IC31 adjuvant.<br>* Other names: H4;Biological: Placebo<br>* Tris buffer saline consisting (10mM Tris and 169mM NaCI at pH7.4)<br>* Other names: Tris Buffered saline;|
| Experimental: AERAS404<br>2 dose placebo | Biological: Placebo<br>* Tris buffer saline consisting (10mM Tris and 169mM NaCI at pH7.4)<br>* Other names: Tris Buffered saline;|
| Experimental: AERAS404 (50mcg H4/100nmol IC31) or Placebo<br>2 dose | Biological: AERAS-404<br>* AERAS 404 (H4:IC31) contains a fusion protein of 2 mycobacterial antigens (Ag85B and TB 10.4) formulated in IC31 adjuvant.<br>* Other names: H4;Biological: Placebo<br>* Tris buffer saline consisting (10mM Tris and 169mM NaCI at pH7.4)<br>* Other names: Tris Buffered saline;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety of one or two injections of two AERAS 404 antigen amounts administered with three different amounts of adjuvant | Serious adverse events (SAE) will be collected on subjects throughout their participation in the study. Solicited and unsolicited AEs will be collected through 28 days after each vaccination.The safety profile of the different antigen/adjuvant treatment regimens will be described. Listings will be provided for all subjects with serious adverse events (SAE). All adverse events and clinically relevant laboratory results will be summarized across time points to examine the relationship between treatment regimens (i.e., number of doses and level of antigen/adjuvant) and key safety endpoints including number (percentage) of solicited and spontaneous adverse events and number (percentage) of subjects with newly abnormal post-vaccination laboratory values based on predefined toxicity criteria. Adverse events will also be summarized by severity and relationship to study vaccine by treatment regimen. | All subjects will be followed for safety and immunogenicity evaluations for 182 days. A total of eleven clinic visits are planned (excluding screening) for all subjects | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the immunogenicity of one or two injections of two AERAS 404 antigen amounts administered with three different amounts of adjuvant. | Assessment of immune response will be based on the percentage of CD4 and CD8 T cells producing any of three cytokines (interferon gamma, IFN-γ; tumor necrosis factor alpha, TNF-α; and/or interleukin-2, IL-2) or any combination of these three cytokines simultaneously in response to stimulation with two the antigenic peptide pools contains 85B and TB10.4 representing the entire amino acid sequences of mycobacterial antigens Ag85B and TB10.4, respectively. Responses will be measured by flow cytometry using a qualified intracellular cytokine staining (ICS) assay | all subjects will have immunology samples taken at 9 time points over 182 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
BCG Vaccinated, HIV Negative