A Study to Evaluate the Safety of AERAS-402 in Adults Recently Treated for Pulmonary TB

Study Overview
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Brief Summary
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This was a double-blind, randomized, placebo-controlled dose-escalation study in adults recently treated for pulmonary TB. The dose of AERAS-402 increased in successive dose groups. Enrollment into a dose group was sequential. Enrollees were stratified based on time from the start of TB treatment. The on-TB-treatment stratum started TB treatment between 1 and 4 months (30 to 120 calendar days) prior to Study Day 0. The post-TB-treatment stratum started TB treatment at least 12 months (360 calendar days) prior to Study Day 0. Subjects were randomized to receive a placebo or AERAS-402 vaccine. In Dose Groups 1 and 2, subjects were randomized to receive a single injection of AERAS-402 or placebo. Dose Group 3 subjects were randomized to receive two injections on study day 0 and study day 42 of AERAS-402 or placebo.

Detailed Description
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A total of 72 subjects were randomized into the study. Subjects were stratified, based on time from the start of TB treatment, into the 'on-TB-treatment' stratum (TB treatment started between 1 and 4 months prior to Study Day 0) or the 'post-TB-treatment' stratum (TB treatment started at least 12 months before Study Day 0). In the on-TB-treatment stratum, 36 subjects were randomized to receive AERAS-402 or placebo as follows: 1 or 2 doses of placebo (N=5); 1 dose of AERAS-402 at 3 x 10^8 vp (N=5) or 3 x 10^9 vp (N=10), or 2 doses of AERAS-402 at 3 x 10^10 vp (N=16). In the post-TB-treatment stratum, 36 subjects were randomized to receive AERAS-402 or placebo as follows: 1 or 2 doses of placebo (N=6); 1 dose of AERAS-402 at 3 x 10^8 vp (N=5) or 3 x 109 vp (N=10), or 2 doses of AERAS-402 at 3 x 10^10 vp (N=15).

Official Title
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A Phase II Double-Blind, Randomized, Placebo-controlled, Dose Escalation Study to Evaluate the Safety of AERAS-402 in Adults Recently Treated for Pulmonary Tuberculosis

Conditions
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Tuberculosis

Intervention / Treatment
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* Biological: Placebo
* Biological: AERAS-402 3 x 10^8 vp
* Biological: AERAS-402 3 x 10^9 vp
* Biological: AERAS-402 3 x 10^10 vp


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is male or female. Is age 18 through 45 years on Study Day 0. Has completed the written informed consent process. Has a history of pulmonary tuberculosis diagnosed by either a sputum smear positive for acid-fast bacilli (AFB) or a sputum culture positive for Mtb. Has initiated effective chemotherapy for tuberculosis between one month (30 days) and four months (120 days) before Study Day 0, with improvement in clinical signs and/or symptoms of disease, OR: has initiated effective chemotherapy for tuberculosis at least 12 months (360 days) before Study Day 0, and is considered cured. For subjects currently receiving chemotherapy for tuberculosis they must have been fully compliant with previously prescribed tuberculosis therapy and agree to complete currently prescribed tuberculosis therapy. Agrees to avoid elective surgery for the full duration of the study. For female subjects: agrees to avoid pregnancy for the full duration of the study. Agrees to stay in contact with the study site for the full duration of the study, providing updated contact information as necessary, and has no current plans to move from the study area during the duration of the study. Has completed simultaneous enrollment in Aeras Vaccine Development Registry Protocol. Exclusion Criteria: Fever ≥37.5°C. Evidence of a new acute illness that may compromise the safety of the subject in the study. Evidence of any significant active infection other than tuberculosis. Evidence of central nervous system tuberculosis or pleural tuberculosis. Previous medical history that may compromise the safety of the subject in the study, including but not limited to: severe impairment of pulmonary function from tuberculosis infection or other pulmonary disease; chronic illness with signs of cardiac or renal failure; suspected progressive neurological disease; or uncontrolled epilepsy or infantile spasms. Evidence of any systemic disease or any acute or chronic illness that may interfere with the evaluation of the safety of the vaccine. History or laboratory evidence of any past, present or future possible immunodeficiency state, including but not limited to any laboratory indication of HIV-1 infection. History of allergic disease or reactions likely to be exacerbated by any component of the study vaccine. Received any investigational drug therapy or vaccine within 182 days before the first dose of study vaccine in this protocol. Received any adenovirus-based vaccine previously. For female subjects: Currently pregnant, lactating/nursing, or a positive serum or urine βhCG Severe anemia, defined as a hemoglobin less than 10 g/dL or a hematocrit less than 30 percent. Urine toxicology screen positive for opiates, cocaine, or amphetamines. Anal intercourse with another man at least one time (with or without condoms). Exchange of goods, money, services or drugs for sex. Use of intravenous drugs. Sexual intercourse or genital contact within the last 12 months with a known HIV positive individual. Vaginal intercourse within the last 12 months without use of a condom with a known user of intravenous drugs. Oral to genital contact within the last 12 months with a known user of intravenous drugs. Vaginal intercourse within the last 12 months without use of a condom with an individual known to have more than one sex partner. Oral to genital contact within the last 12 months with an individual known to have more than one sex partner.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo control: 1.0 mL sterile buffer containing 20 mM Tris buffer, 2 mM MgCl2, 25 mM NaCl, 10% w/v sucrose, 0.02% w/v PS-80 (polysorbate-80, non animal source) and water. | Biological: Placebo<br>* This is the identical buffer solution in which AERAS-402 is formulated. The placebo (1.0 mL volume) was administered by intramuscular (IM) injection to the deltoid area on Study Day 0 for groups 1 and 2 and Study Day 0 and 42 for group 3.<br>* Other names: Sterile buffer;|
| Experimental: AERAS-402 3 x 10^8 vp<br>AERAS-402: 1.0 mL containing 3 x 10^8 vp/mL suspended in 20 mM Tris buffer, 2 mM MgCl2, 25 mM NaCl, 10% w/v sucrose, 0.02% w/v PS-80 (polysorbate-80, non animal source) and water. | Biological: AERAS-402 3 x 10^8 vp<br>* AERAS-402 was administered by single intramuscular (IM) injection to the deltoid area on Study Day 0<br>* Other names: AERAS-402;|
| Experimental: AERAS-402 3 x 10^9 vp<br>AERAS-402: 1.0 mL containing 3 x 10^9 vp/mL suspended in 20 mM Tris buffer, 2 mM MgCl2, 25 mM NaCl, 10% w/v sucrose, 0.02% w/v PS-80 (polysorbate-80, non animal source) and water. | Biological: AERAS-402 3 x 10^9 vp<br>* AERAS-402 was administered by single intramuscular (IM) injection to the deltoid area on Study Day 0<br>* Other names: AERAS-402;|
| Experimental: AERAS-402 3 x 10^10 vp<br>AERAS-402: 1.0 mL containing 3 x 10^10 vp/mL suspended in 20 mM Tris buffer, 2 mM MgCl2, 25 mM NaCl, 10% w/v sucrose, 0.02% w/v PS-80 (polysorbate-80, non animal source) and water. | Biological: AERAS-402 3 x 10^10 vp<br>* AERAS-402 was administered by intramuscular (IM) injection to the deltoid area on Study Days 0 and 42.<br>* Other names: AERAS-402;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Solicited and Unsolicited AEs | All adverse events will be summarized to examine the relationship between dose levels including number (percentage) of solicited and unsolicited adverse events (AEs), and number (percentage) of subjects with newly abnormal post-vaccination laboratory values based on predefined toxicity criteria. | 182 days | 
| Forced Expiratory Volume in One Second (FEV1) | Maximum number of subjects with deterioration >10% from baseline, at any time point. in forced expiratory volume in one second (FEV1) | 182 days | 
| Forced Vital Capacity (FVC) | Maximum number of subjects with deterioration >10% from baseline, at any time point, in forced vital capacity (FVC) | 182 days | 
| Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) | Maximum number of subjects with deterioration >15% from baseline, at any time point, in diffusing capacity of the lung for carbon monoxide (DLCO) | 182 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity of AERAS-402 Based on the Percentage of CD4 Cells of Participants in the on TB Treatment Stratum | Assessment of immune response to AERAS-402 was based on the percentage of CD4 and CD8 T cells producing any combination of three cytokines (IFN-γ, TNF-α, and/or IL-2) following stimulation with mycobacterial peptide pools derived from and representing the entire amino acid sequences of mycobacterial antigens Ag85A, Ag85B, and TB10.4. Responses were measured by the intracellular cytokine staining (ICS) assay using flow cytometry. | 42 days post dose | 
| Immunogenicity of AERAS-402 Based on the Percentage of CD8 Cells of Participants in the on TB Treatment Stratum | Assessment of immune response to AERAS-402 was based on the percentage of CD4 and CD8 T cells producing any combination of three cytokines (IFN-γ, TNF-α, and/or IL-2) following stimulation with mycobacterial peptide pools derived from and representing the entire amino acid sequences of mycobacterial antigens Ag85A, Ag85B, and TB10.4. Responses were measured by the intracellular cytokine staining (ICS) assay using flow cytometry. | 42 days post dose | 
| Immunogenicity of AERAS-402 Based on the Percentage of CD4 Cells of Participants in the Post TB Treatment Stratum | Assessment of immune response to AERAS-402 was based on the percentage of CD4 and CD8 T cells producing any combination of three cytokines (IFN-γ, TNF-α, and/or IL-2) following stimulation with mycobacterial peptide pools derived from and representing the entire amino acid sequences of mycobacterial antigens Ag85A, Ag85B, and TB10.4. Responses were measured by the intracellular cytokine staining (ICS) assay using flow cytometry. | 42 days post dose | 
| Immunogenicity of AERAS-402 Based on the Percentage of CD8 Cells of Participants in the Post TB Treatment Stratum | Assessment of immune response to AERAS-402 was based on the percentage of CD4 and CD8 T cells producing any combination of three cytokines (IFN-γ, TNF-α, and/or IL-2) following stimulation with mycobacterial peptide pools derived from and representing the entire amino acid sequences of mycobacterial antigens Ag85A, Ag85B, and TB10.4. Responses were measured by the intracellular cytokine staining (ICS) assay using flow cytometry. | 42 days post dose |