A Phase I Study to Evaluate Safety and Immunogenicity of AERAS 404 (C-011-404)

Study Overview
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Brief Summary
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This Phase I study will be conducted as a randomized, placebo-controlled, double-blind, dose-escalation study in four groups of healthy adult male and female subjects who are BCG-vaccinated, HIV-negative, and have no evidence of tuberculosis infection. The study will be conducted at one or two sites located in South Africa. The purpose is to evaluate the safety and immunogenicity of two injections of AERAS 404 prepared with four escalating amounts of antigen in healthy adult male and female subjects who are BCG-vaccinated, HIV-negative, and have no evidence of tuberculosis infection.

Detailed Description
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This Phase I study will be conducted as a randomized, placebo-controlled, double-blind, dose-escalation study in four groups of healthy adult male and female subjects who are BCG-vaccinated, HIV-negative, and have no evidence of tuberculosis infection. The study will be conducted at one or two sites located in South Africa. Forty subjects will be sequentially enrolled into one of four study groups (i.e., Group 1, Group 2, Group 3, or Group 4) based on time of completion of screening, with 10 subjects enrolled into each group. Within each study group, subjects will be randomized to a treatment regimen of either AERAS-404 or placebo control administered by intramuscular injection on Study Day 0 and Study Day 56. All subjects will receive the same treatment on Study Day 0 as they receive on Study Day 56. The dose of antigen will increase between study groups. 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.

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

Conditions
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Tuberculosis

Intervention / Treatment
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* Biological: AERAS-404 (mcg H4/nmol IC31)
* Biological: Sterile buffer containing 10 mmol/L tris and 169 mmol/L NaCl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Subjects must have met all of the following criteria: Had completed written informed consent Was male or female Was age 18 through 50 years on Study Day 0 Had BCG vaccination at least 5 years ago, documented through medical history or presence of scar Had general good health, confirmed by medical history and physical examination Had a Body Mass Index (BMI) between 19 and 33 (weight in kg/[height in m]2) Agreed to complete a follow-up period of 182 days as required by the protocol Females: Agreed to avoid pregnancy from 28 days prior to Study Day 0 through the follow-up period of 182 days. Agreed to avoid elective surgery for the duration of the study Agreed to stay in contact with the investigative site for the duration of the study Had completed simultaneous enrollment in Aeras Vaccine Development Registry protocol Exclusion Criteria Subjects must not have: Acute illness on Study Day 0 Oral temperature equal to or greater than 37.5 degrees C on Study Day 0 Evidence of significant active infection Used immunosuppressive medication within 42 days before Study Day 0 (inhaled and topical corticosteroids are permitted) 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 inactivated influenza vaccine or inactivated tick-borne encephalitis vaccine within 14 days before entry into the study, or any other standard vaccine within 42 days before Study Day 0 (the use of licensed drugs or vaccines medically indicated during the study interval was permitted) Current chronic drug therapy including hormone replacement such as thyroxin, insulin, etc. Estrogen and progesterone replacement and contraceptives were acceptable. History or laboratory evidence of any past, present or future possible immunodeficiency state which included (but was not limited to) any laboratory indication of HIV infection History of allergic disease or reactions, including eczema, likely to be exacerbated by any component of the study vaccine Previous medical history that may have compromised the safety of the subject in the study Evidence of a new acute illness that may have compromised the safety of the subject in the study Evidence of chronic hepatitis (e.g., hepatitis B core antibody or hepatitis C antibody) Inability to discontinue daily medications except contraceptives during the study period History of alcohol or drug abuse within the past 2 years Tobacco or cannabis smoking 3 or more days per week Positive urine test for illicit drugs (opiates, cocaine, amphetamines) History or evidence of any systemic disease on physical examination or any acute or chronic illness that, in the opinion of the investigator, may have interfered with the evaluation of the safety or immunogenicity of the vaccine, including axillary lymphadenopathy History or evidence (including chest X-ray) of active tuberculosis Shared a residence within the last year with an individual on anti-tuberculosis treatment or with culture or smear positive tuberculosis All females: Positive urine pregnancy test during screening; positive serum pregnancy test on the day of study vaccination; were nursing Abnormal (per local laboratory parameters) chemistry, hematology or urinalysis obtained within 36 hours prior to randomization. Laboratory evidence of Mtb infection, defined as a positive QuantiFERON-TB Gold (QFT-G) test. History of a positive tuberculin skin test within the past ten years (defined according to local guidelines). Received a tuberculin skin test within 3 months (90 days) prior to Study Day 0.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AERAS-404 (mcg H4/nmol IC31) 5/500<br>H4 antigen (supplied in 4 different concentrations): 1.0 mL containing H4 antigen at 50, 150, 500, or 1500 mcg/mL in 10 mmol/L tris and 5% glycerol IC31 Adjuvant (supplied in 1 concentration): 0.8 mL containing IC31 adjuvant at 1250 nmol/mL, in 10 mmol/L tris and 169 mmol/L NaCl | Biological: AERAS-404 (mcg H4/nmol IC31)<br>* Dose escalation<br>* Other names: AERAS-404;|
| Experimental: AERAS-404 (mcg H4/nmol IC31) 15/500<br>H4 antigen (supplied in 4 different concentrations): 1.0 mL containing H4 antigen at 50, 150, 500, or 1500 mcg/mL in 10 mmol/L tris and 5% glycerol IC31 Adjuvant (supplied in 1 concentration): 0.8 mL containing IC31 adjuvant at 1250 nmol/mL, in 10 mmol/L tris and 169 mmol/L NaCl | Biological: AERAS-404 (mcg H4/nmol IC31)<br>* Dose escalation<br>* Other names: AERAS-404;|
| Experimental: AERAS-404 (mcg H4/nmol IC31) 50/500<br>H4 antigen (supplied in 4 different concentrations): 1.0 mL containing H4 antigen at 50, 150, 500, or 1500 mcg/mL in 10 mmol/L tris and 5% glycerol IC31 Adjuvant (supplied in 1 concentration): 0.8 mL containing IC31 adjuvant at 1250 nmol/mL, in 10 mmol/L tris and 169 mmol/L NaCl | Biological: AERAS-404 (mcg H4/nmol IC31)<br>* Dose escalation<br>* Other names: AERAS-404;|
| Experimental: AERAS-404 (mcg H4/nmol IC31) 150/500<br>H4 antigen (supplied in 4 different concentrations): 1.0 mL containing H4 antigen at 50, 150, 500, or 1500 mcg/mL in 10 mmol/L tris and 5% glycerol IC31 Adjuvant (supplied in 1 concentration): 0.8 mL containing IC31 adjuvant at 1250 nmol/mL, in 10 mmol/L tris and 169 mmol/L NaCl | Biological: AERAS-404 (mcg H4/nmol IC31)<br>* Dose escalation<br>* Other names: AERAS-404;|
| Placebo Comparator: Sterile buffer containing 10 mmol/L tris and 169 mmol/L NaCl<br>Placebo: Sterile buffer containing 10 mmol/L tris and 169 mmol/L NaCl. This is the identical buffer solution in which IC31 is formulated. | Biological: Sterile buffer containing 10 mmol/L tris and 169 mmol/L NaCl<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety of two injections of AERAS 404 prepared with four escalating amounts of antigen in healthy adult subjects. Safety will be measured by number (percentage) and severity of SAEs. | The safety profile will be described by treatment regimen. Serious adverse events (SAE) will be collected on subjects throughout their participation in the study. Solicited and unsolicited adverse events will be captured for 28 days after each vaccination. The number (percentage) of subjects with any adverse events (including solicited, unsolicited and serious adverse events) will be summarized by MedRA system organ class (SOC) and preferred term (PT). Additional summaries will present the number (percentage) of subjects with any adverse events by severity and by relationship to study vaccine. The number (percentage) of subjects with post-vaccination clinical laboratory values or vital sign values recorded as newly abnormal following study vaccination and meeting toxicity criteria will be tabulated at each post-vaccination point and overall. | Solicited and unsolicited AEs until study day 182 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the immunogenicity of two injections of AERAS 404 prepared with four escalating amounts of antigen in healthy adult subjects. Immune response will be based on percentage of CD4+ and CD8+ cells. | The primary response will be measured by flow cytometry in the Intracellular cytokine staining (ICS) assay. Immune responses will be based on percentage of CD4+ and CD8+ T cells that produced one, two, or three cytokines (IFN-gamma, TNF, and/or IL-2) in response to stimulation with one of the 2 antigenic peptide pool (Ag85B and TB10.4) derived from and representing the entire amino acid sequences of teh mycobacterial antigens Ag85B and TB10.4. | 182 days |