Safety, Tolerability and Immunogenicity Study of AV7909 Anthrax Vaccine in Healthy Adults

Study Overview
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Brief Summary
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The purpose of this Phase 1 clinical trial is to evaluate the safety, tolerability, and immunogenicity of AV7909 anthrax vaccine in healthy adults. In this study, healthy male and female subjects between 18 and 50 years of age will receive vaccinations via the intramuscular (IM) route at Days 0 and 14. Safety and tolerability will be evaluated via laboratory tests, physical examinations, vital signs, adverse events (AEs), concomitant medications, and local and systemic signs and symptoms of reactogenicity.

Detailed Description
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AV7909 is a new vaccine which is a combination of BioThrax (also called anthrax vaccine, adsorbed or AVA), a FDA-licensed vaccine, and CPG 7909. CPG 7909 is a synthetic short DNA sequence that has been shown to be an effective vaccine adjuvant, and one which increases the speed and the degree of the immune response to Protective Antigen (PA), the major vaccine antigen. In the current study, the safety, tolerability, and antibody response to PA will be studied for four different combinations of AVA and CPG 7909, and compared to both AVA and a saline placebo. All formulations of AV7909 have the same or less AVA than the licensed AVA vaccine and all have less CPG 7909 per dose than the formulation used in the first Phase I volunteer study of CPG 7909 combined with AVA.

Official Title
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A Parallel-arm, Double-blind, Randomized, Placebo-controlled, Dose-ranging Clinical Trial Evaluating the Safety, Tolerability and Immunogenicity of AV7909 in Healthy Adults

Conditions
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Bacillus Anthracis (Anthrax) Infection

Intervention / Treatment
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* Biological: BioThrax
* Biological: AV7909 Formulation 1
* Biological: AV7909 Formulation 2
* Biological: AV7909 Formulation 3
* Biological: AV7909 Formulation 4
* Drug: Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be between 18 and 50 years of age, inclusive, at the time of enrollment. Be in good health as determined by the investigator from medical history and a physical examination. If a pre-menopausal female, must be using acceptable methods of birth control. Have all hematology and chemistry parameters (measured at Screening) within the laboratory's normal range. Have negative values for the following tests at Screening: Hepatitis C antibody, anti-Human Immunodeficiency Virus (Anti-HIV-1/-2/-O), and anti-Hepatitis B Core Antigen (Anti-HBc). Be willing and capable of complying with all aspects of the protocol through completion of the required visits. Have not donated blood in the preceding 8 weeks and are willing to not donate blood or plasma within 56 days after dosing. Have adequate venous access for repeat phlebotomies. Have read, understood and signed an informed consent form. Exclusion Criteria: Key Exclusion Criteria: A known anaphylactic response, severe systematic response, or serious hypersensitivity reaction to a prior immunization. Prior immunization with anthrax vaccine, recombinant Protective Antigen (rPA) vaccine, or known exposure to anthrax organisms. Have previously served in the military or plans to enlist in the military from Screening through Day 84. Have participated in anthrax therapeutic or vaccine trials (monoclonal anti-protective antigen (PA) or anthrax immune globulins or anthrax vaccines). Participation in any investigational clinical trial within 30 days preceding the Screening visit or planning to participate in a clinical trial requiring dosing through the Day 194 visit. A history of drug or alcohol abuse within 12 months prior to Screening, or a positive result on a urine drug screen for amphetamines, barbiturates, benzodiazepines, cocaine, marijuana, methylenedioxymethamphetamine opiates, oxycodone, phencyclidine, propoxyphene, or tricyclic antidepressants. Blood pressure greater than 145 millimeters of mercury (mmHg) systolic or 90 mmHg diastolic. Past history of significant autoimmune disease such as rheumatoid arthritis, lupus erythematous, psoriasis, glomerulonephritis, or autoimmune thyroiditis. A medical condition that, in the opinion of the Principal Investigator (PI), could adversely impact the subject's participation, safety, or conduct of the study.

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 |
| --- | --- |
| Active Comparator: BioThrax<br>BioThrax, 0.5 mL AVA per dose | Biological: BioThrax<br>* BioThrax<br>* Other names: Anthrax Vaccine Adsorbed (AVA);|
| Experimental: AV7909 Formulation 1<br>0.5 mL AVA + 0.5 mg CPG 7909 per 0.5 mL dose | Biological: AV7909 Formulation 1<br>* AV7909 Formulation 1<br>|
| Experimental: AV7909 Formulation 2<br>0.5 mL AVA + 0.25 mg CPG 7909 per 0.5 mL dose | Biological: AV7909 Formulation 2<br>* AV7909 Formulation 2<br>|
| Experimental: AV7909 Formulation 3<br>0.25 mL AVA + 0.5 mg CPG 7909 per 0.5 mL dose | Biological: AV7909 Formulation 3<br>* AV7909 Formulation 3<br>|
| Experimental: AV7909 Formulation 4<br>0.25 mL AVA + 0.25 mg CPG 7909 per 0.5 mL dose | Biological: AV7909 Formulation 4<br>* AV7909 Formulation 4<br>|
| Placebo Comparator: Control<br>Saline control | Drug: Control<br>* Saline control<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Injection Site Reactions From Subject Diary Cards by Injection and Severity (Mild, Moderate or Severe) Following the First Vaccination (Day 0) | Subjects recorded solicited injection site reactions (ISRs) (redness, swelling, tenderness, pain, itching, arm motion limitation) on diary cards for 7 days following the first injection (Day 0). All local reactions collected by subjects on diary cards were recorded as adverse events. Severity of ISR was assessed using a grading scale based on FDA Guidance Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Swelling/edema and redness/erythema were graded by the greater of two perpendicular measurements of diameter rated as follows: Grade 0: none Grade 1: <3 cm Grade 2: 3 to 10 cm Grade 3: >10 cm For all other ISRs, the following scale was used: Grade 0: not present Grade 1: present with no limitation of activity Grade 2: interfering with daily activities or requiring non-narcotic treatment Grade 3: preventing normal daily activities or requiring narcotic analgesia | Days 0-6 | 
| Percentage of Subjects With Injection Site Reactions From Subject Diary Cards by Injection and Severity (Mild, Moderate or Severe) Following the First Vaccination (Day 0) | Subjects recorded solicited injection site reactions (ISRs) (redness, swelling, tenderness, pain, itching, arm motion limitation) on diary cards for 7 days following the first injection (Day 0). All local reactions collected by subjects on diary cards were recorded as adverse events. Severity of ISR was assessed using a grading scale based on FDA Guidance Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Swelling/edema and redness/erythema were graded by the greater of two perpendicular measurements of diameter rated as follows: Grade 0: none Grade 1: <3 cm Grade 2: 3 to 10 cm Grade 3: >10 cm For all other ISRs, the following scale was used: Grade 0: not present Grade 1: present with no limitation of activity Grade 2: interfering with daily activities or requiring non-narcotic treatment Grade 3: preventing normal daily activities or requiring narcotic analgesia | Days 0-6 | 
| Incidence of Injection Site Reactions From Subject Diary Cards by Injection and Severity (Mild, Moderate or Severe) Following the Second Vaccination (Day 14) | Subjects recorded solicited injection site reactions (ISRs) (redness, swelling, tenderness, pain, itching, arm motion limitation) on diary cards for 7 days following the second injection (Day 14). All local reactions collected by subjects on diary cards were recorded as adverse events. Severity of ISR was assessed using a grading scale based on FDA Guidance Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Swelling/edema and redness/erythema were graded by the greater of two perpendicular measurements of diameter rated as follows: Grade 0: none Grade 1: <3 cm Grade 2: 3 to 10 cm Grade 3: >10 cm For all other ISRs, the following scale was used: Grade 0: not present Grade 1: present with no limitation of activity Grade 2: interfering with daily activities or requiring non-narcotic treatment Grade 3: preventing normal daily activities or requiring narcotic analgesia | Days 14-20 | 
| Percentage of Subjects With Injection Site Reactions From Subject Diary Cards by Injection and Severity (Mild, Moderate or Severe) Following the Second Vaccination (Day 14) | Subjects recorded solicited injection site reactions (ISRs) (redness, swelling, tenderness, pain, itching, arm motion limitation) on diary cards for 7 days following the second injection (Day 14). All local reactions collected by subjects on diary cards were recorded as adverse events. Severity of ISR was assessed using a grading scale based on FDA Guidance Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Swelling/edema and redness/erythema were graded by the greater of two perpendicular measurements of diameter rated as follows: Grade 0: none Grade 1: <3 cm Grade 2: 3 to 10 cm Grade 3: >10 cm For all other ISRs, the following scale was used: Grade 0: not present Grade 1: present with no limitation of activity Grade 2: interfering with daily activities or requiring non-narcotic treatment Grade 3: preventing normal daily activities or requiring narcotic analgesia | Days 14-20 | 
| Incidence of Systemic Reactions From Subject Diary Cards by Injection and Severity (Mild, Moderate or Severe) Following the First Injection (Day 0) | Subjects recorded solicited systemic reactions (fever, fatigue, muscle aching, headache, nausea/GI upset) on diary cards for 7 days following each of two injections (Days 0 and 14) All systemic reactions collected by subjects on diary cards were recorded as adverse events. Severity of systemic reactions was assessed using a grading scale based on FDA Guidance titled Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Toxicity grades for fever were derived from body temperature using the following scale: Grade 0: <100°F Grade 1: 100.0 - 101.5°F Grade 2: 101.6 - 102.9°F ; Grade 3: 103.0 - 105.0°F For all other systemic reactions, the following scale was used: Grade 0: not present Grade 1: present with no limitation of activity Grade 2: interfering with daily activities or requiring non-narcotic treatment Grade 3: preventing normal daily activities or requiring narcotic analgesia | Days 0-6 | 
| Percentage of Subjects With Systemic Reactions From Subject Diary Cards by Injection and Severity (Mild, Moderate or Severe) Following the First Injection (Day 0) | Subjects recorded solicited systemic reactions (fever, fatigue, muscle aching, headache, nausea/GI upset) on diary cards for 7 days following each of two injections (Days 0 and 14) All systemic reactions collected by subjects on diary cards were recorded as adverse events. Severity of systemic reactions was assessed using a grading scale based on FDA Guidance titled Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Toxicity grades for fever were derived from body temperature using the following scale: Grade 0: <100°F Grade 1: 100.0 - 101.5°F Grade 2: 101.6 - 102.9°F ; Grade 3: 103.0 - 105.0°F For all other systemic reactions, the following scale was used: Grade 0: not present Grade 1: present with no limitation of activity Grade 2: interfering with daily activities or requiring non-narcotic treatment Grade 3: preventing normal daily activities or requiring narcotic analgesia | Days 0-6 | 
| Incidence of Systemic Reactions From Subject Diary Cards by Injection and Severity (Mild, Moderate or Severe) Following the Second Injection (Day 14) | Subjects recorded solicited systemic reactions (fever, fatigue, muscle aching, headache, nausea/GI upset) on diary cards for 7 days following each of two injections (Days 0 and 14) All systemic reactions collected by subjects on diary cards were recorded as adverse events. Severity of systemic reactions was assessed using a grading scale based on FDA Guidance titled Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Toxicity grades for fever were derived from body temperature using the following scale: Grade 0: <100°F Grade 1: 100.0 - 101.5°F Grade 2: 101.6 - 102.9°F ; Grade 3: 103.0 - 105.0°F For all other systemic reactions, the following scale was used: Grade 0: not present Grade 1: present with no limitation of activity Grade 2: interfering with daily activities or requiring non-narcotic treatment Grade 3: preventing normal daily activities or requiring narcotic analgesia | Days 14-20 | 
| Percentage of Subjects With Systemic Reactions From Subject Diary Cards by Injection and Severity (Mild, Moderate or Severe) Following the Second Injection (Day 14) | Subjects recorded solicited systemic reactions (fever, fatigue, muscle aching, headache, nausea/GI upset) on diary cards for 7 days following each of two injections (Days 0 and 14) All systemic reactions collected by subjects on diary cards were recorded as adverse events. Severity of systemic reactions was assessed using a grading scale based on FDA Guidance titled Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Toxicity grades for fever were derived from body temperature using the following scale: Grade 0: <100°F Grade 1: 100.0 - 101.5°F Grade 2: 101.6 - 102.9°F ; Grade 3: 103.0 - 105.0°F For all other systemic reactions, the following scale was used: Grade 0: not present Grade 1: present with no limitation of activity Grade 2: interfering with daily activities or requiring non-narcotic treatment Grade 3: preventing normal daily activities or requiring narcotic analgesia | Days 14-20 | 
| Incidence of Hematology, Serum Chemistry, and Urinalysis Abnormalities Reported as Adverse Events | Hematology test included hemoglobin, hematocrit, white blood cell count, absolute lymphocyte count, absolute neutrophil count, absolute eosinophil count, and platelet count. Serum chemistry test included albumin, alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine, glucose, calcium, potassium, alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase. Urinalysis included appearance, color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, urobilinogen, and occult blood. Hematology tests were done on Days 0, 1, 2, 7, 28, and 56. Serum chemistry tests and urinalysis were done on Days 0, 7, 28, and 56. | Days 0-56 | 
| Percentage of Subjects With Hematology, Serum Chemistry, and Urinalysis Abnormalities Reported as Adverse Events | Hematology test included hemoglobin, hematocrit, white blood cell count, absolute lymphocyte count, absolute neutrophil count, absolute eosinophil count, and platelet count. Serum chemistry test included albumin, alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine, glucose, calcium, potassium, alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase. Urinalysis included appearance, color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, urobilinogen, and occult blood. Hematology tests were done on Days 0, 1, 2, 7, 28, and 56. Serum chemistry tests and urinalysis were done on Days 0, 7, 28, and 56. | Days 0-56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak TNA NF50 GMT for All Subjects in the Immunogenicity Population and by Gender After IM Administration of Investigational Product on Days 0 and 14. | Toxin neutralizing antibody (TNA) levels in blinded serum samples were measured using a validated anthrax lethal toxin neutralization assay. The primary assay endpoint was the 50% neutralization factor (TNA NF50). TNA NF50 is calculated as the ratio of the 50% effective dose (ED50) of the test sample to the ED50 of a reference serum. Values below the lower limit of quantitation (LLOQ) of the assay (ED50 of 33) were replaced with one-half the LLOQ (ED50 of 16.5) for calculation of geometric mean titer (GMT) and statistical analysis. GMT is based on log transformation. | Day 0 (pre-dose), 7, 14 (pre-dose), 21, 28, 35, 42, 56, 70, and 84. | 
| Median Time to Peak TNA NF50 GMT for All Subjects in the Immunogenicity Population and by Gender After IM Administration of Investigational Product on Days 0 and 14. | Toxin neutralizing antibody (TNA) levels in blinded serum samples were measured using a validated anthrax lethal toxin neutralization assay. The primary assay endpoint was the 50% neutralization factor (TNA NF50). TNA NF50 is calculated as the ratio of the 50% effective dose (ED50) of the test sample to the ED50 of a reference serum. Values below the LLOQ of the assay (ED50 of 33) were replaced with one-half the LLOQ (ED50 of 16.5) for calculation of geometric mean titer (GMT) and statistical analysis. GMT is based on log transformation. | Day 0 (pre-dose), 7, 14 (pre-dose), 21, 28, 35, 42, 56, 70, and 84. | 
| TNA NF50 GMTs Across Study Days After IM Administration of Investigational Product on Days 0 and 14. | Toxin neutralizing antibody (TNA) levels in blinded serum samples were measured using a validated anthrax lethal toxin neutralization assay. The primary assay endpoint was the 50% neutralization factor (TNA NF50). TNA NF50 is calculated as the ratio of the 50% effective dose (ED50) of the test sample to the ED50 of a reference serum. Values below the LLOQ of the assay (ED50 of 33) were replaced with one-half the LLOQ (ED50 of 16.5) for calculation of geometric mean titer (GMT) and statistical analysis. GMT is based on log transformation. | Day 0 (pre-dose), 7, 14 (pre-dose), 21, 28, 35, 42, 56, 70, and 84. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AVA, AV7909, Anthrax vaccine