Anthrax AV7909 Liquid vs Lyophilized

Study Overview
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Brief Summary
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This is a randomized, parallel-group, double-blind, Phase 1 study designed to assess safety, tolerability and immunogenicity 2 formulations of adjuvanted anthrax vaccine (AV7909), lyophilized and liquid. Forty healthy young adults, 18 to 45 years old, inclusive, who meet all eligibility criteria, will be randomly allocated to one of two study groups in a 1:1 ratio: 20 will receive AV7909 as the thermostable lyophilized product and 20 will receive AV7909 as the liquid product. The vaccines will be given intramuscularly in a 2-dose schedule, 2 weeks apart. Safety will be assessed by evaluation of non-serious unsolicited Adverse Events, Serious Adverse Events (SAEs), Medically Attended Adverse Events (MAAEs), Adverse Events of Special Interest (AESIs) [the AESIs collected in this study are Potentially Immune-Mediated Medical Conditions (PIMMCs)], and by laboratory evaluations. Reactogenicity will be measured by the occurrence of solicited injection site and systemic reactions in the week after each study vaccination. Immunogenicity testing will include performing serological assays to assess for toxin neutralizing antibodies (reported as ED50 and NF50), the gold standard assay for assessing response and protection following anthrax vaccines, prior to vaccination and on approximately Days 8, 15, 22, 29, 64, 195, and 380. In addition, anti-PA IgG antibodies will be measured by ELISA from the serum of participants, on those same days. The primary safety objective of this study is to assess the safety of lyophilized and liquid formulations of AV7909. The primary tolerability objective is to assess the tolerability of lyophilized and liquid formulations of AV7909.

Detailed Description
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This is a randomized, parallel-group, double-blind, Phase 1 study designed to assess safety, tolerability and immunogenicity of 2 formulations of adjuvanted anthrax vaccine (AV7909), lyophilized and liquid. Forty healthy young adults, 18 to 45 years old, inclusive, who meet all eligibility criteria, will be randomly allocated to one of two study groups in a 1:1 ratio: 20 will receive AV7909 as the thermostable lyophilized product and 20 will receive AV7909 as the liquid product. Stratification by age category and by gender will assure that near equal numbers of younger (18-30 years) and older (31-45 years) males and females are assigned to each vaccine. The vaccines will be given intramuscularly in a 2-dose schedule, 2 weeks apart. Safety will be assessed by evaluation of non-serious unsolicited Adverse Events, Serious Adverse Events (SAEs), Medically Attended Adverse Events (MAAEs), Adverse Events of Special Interest (AESIs) [the AESIs collected in this study are Potentially Immune-Mediated Medical Conditions (PIMMCs)], and by laboratory evaluations. Reactogenicity will be measured by the occurrence of solicited injection site and systemic reactions in the week after each study vaccination. Immunogenicity testing will include performing serological assays to assess for toxin neutralizing antibodies (reported as ED50 and NF50), the gold standard assay for assessing response and protection following anthrax vaccines, prior to vaccination and on approximately Days 8, 15, 22, 29, 64, 195, and 380. In addition, anti-PA IgG antibodies will be measured by ELISA from the serum of participants, on those same days. The primary safety objective of this study is to assess the safety of lyophilized and liquid formulations of AV7909. The primary tolerability objective is to assess the tolerability of lyophilized and liquid formulations of AV7909. The secondary immunogenicity objective of this study is to obtain initial estimate of comparative immunogenicity of liquid and lyophilized formulations of AV7909.

Official Title
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A Phase 1, Randomized, Parallel-Group, Double-Blind Trial of AV7909 (Liquid) and Thermostable AV7909 (Lyophilized) in Healthy Adult Volunteers

Conditions
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Anthrax, Anthrax Immunisation

Intervention / Treatment
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* Biological: AV7909
* Biological: AV7909


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent prior to initiation of any study procedures. Understand and comply with planned study procedures, including completion of the electronic memory aid, and be available for all study visits. Agree to the collection of venous blood, per protocol. Have adequate venous access for phlebotomies. Be a male or non-pregnant female, 18 to 45 years of age, inclusive, at the time of enrollment. Be in good health.* * As determined by medical history and physical examination to evaluate acute or currently ongoing chronic medical diagnoses or conditions, which would affect the assessment of the safety of participants or the immunogenicity of study vaccinations. Chronic medical diagnoses or conditions, defined as those that have been present for at least 90 days, should be stable (not worsening) for the last 60 days (no hospitalizations, emergency room or urgent care for condition, or invasive medical procedure and no adverse symptoms that need medical intervention such as medication change indicative of worsening/supplemental oxygen). This includes no change in chronic prescription medication, dose or frequency, indicative of worsening disease, in the 60 days prior to enrollment. Any prescription change that is due to change of health care provider, insurance company, etc., or that is done for financial reasons, will not be considered a deviation of this inclusion criterion. Participants may be on chronic or as needed (prn) medications if, in the opinion of the site PI or appropriate sub-investigator, they pose no additional risk to participant safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening or treatment of continued symptoms of medical diagnosis or condition. Herbals, vitamins, and supplements are permitted. Have an oral temperature less than 100.0 degrees Fahrenheit. Have a pulse 51 to 100 beats per minute, inclusive. Have a systolic blood pressure 85 to 140 mmHg, inclusive. Have a diastolic blood pressure 55 to 90 mmHg, inclusive. Have a calculated body mass index (BMI) less than or equal to 35.0 kg/m2 at screening. Screening laboratories are within acceptable parameters: BUN <23 mg/dL Serum creatinine (female) <1.3 mg/dL Serum creatinine (male) < 1.4 mg/dL Alkaline phosphatase (female) <147 U/L Alkaline phosphatase (male) <192 U/L ALT (aka SGPT) <68 U/L Total bilirubin < 1.3 mg/dL Hemoglobin (female) >10.9 g/dL Hemoglobin (male) > 12.4 g/dL White blood cell count 3000-12,000 cells/mm3 Absolute eosinophil count <1201 cells/mm3 Absolute neutrophil count >1200 cells/mm3 Platelets >126,000 cells/mm3 Hemoglobin A1C <6.5% Urine for Drugs of Abuse (amphetamines, barbiturates, benzodiazepines, cocaine, methadone, opiates, oxycodone/oxymorphone, phencyclidine (PCP), and propoxyphene). All negative HBsAg Non-reactive HCV antibodies Negative HIV 4th generation test Negative Have no clinically significant findings on 12-lead electrocardiogram.* * Clinical significance will be determined by a cardiologist. Examples of findings that will lead to exclusion are significant left ventricular hypertrophy, right or left bundle branch block, advanced A-V heart block, non-sinus rhythm (excluding isolated premature atrial contractions), pathologic Q wave abnormalities, significant ST-T wave changes, prolonged QTc interval. Heterosexually active females of childbearing potential* must use an acceptable contraception method** from at least 30 days before the first until 60 days after the second study vaccination. Not sterilized via bilateral oophorectomy, salpingectomy, hysterectomy, or successful Essure(R) placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or <1 year has passed since the last menses, if menopausal. Includes full abstinence from sexual intercourse with a male partner, monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more or shown to be azoospermic prior to the participant receiving the study vaccination, barrier methods such as condoms or diaphragms/cervical cap, intrauterine devices, NuvaRing(R), tubal ligation, and licensed hormonal methods such as implants, injectables or oral contraceptives (the pill). Females of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test within 24 hours prior to each study vaccination. For a female with potential to become pregnant, she understands that in the event of pregnancy during the study she will be asked to allow us to follow her during pregnancy through outcome. Must agree to have blood collected, stored, and potentially used for auto-antibody studies (if a suspected Potentially Immune-Mediated Medical Conditions (PIMMC) occurs in this participant). Exclusion Criteria: Have an acute illness*, as determined by the site principal investigator (PI) or appropriate sub-investigator, within 72 hours prior to study vaccination. *An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the site PI or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety parameters and systemic reactogenicity events as required by the protocol. Have any medical disease or condition that, in the opinion of the site PI or appropriate sub-investigator, is a contraindication to study participation.* *Including acute, subacute, intermittent, or chronic medical disease or condition that would place the participant at an unacceptable risk of injury, render the participant unable to meet the requirements of the protocol, or may interfere with the evaluation of responses or the participant's successful completion of this trial. Have immunosuppression as a result of an underlying illness or treatment, a recent history or current use of immunosuppressive or immunomodulating disease therapy.* *These include oral or parenteral (including intra-articular) corticosteroids of any dose within 30 days prior to study vaccination, or high-dose inhaled corticosteroids within 30 days prior to study vaccination, with high-dose defined as per age as using inhaled high-dose per reference chart in the National Heart, Lung and Blood Institute Guidelines for the Diagnosis and Management of Asthma (EPR-3) or other lists published in UPTODATE. Intranasal corticosteroids are not exclusionary. Low and moderate potency topical corticosteroids are permitted. Use of anticancer chemotherapy or radiation therapy (cytotoxic) within 3 years prior to study vaccination. Have known active or recently active (12 months) neoplastic disease or a history of any hematologic malignancy. Non-melanoma treated skin cancers are permitted. Have known human immunodeficiency virus (HIV), chronic hepatitis B, or hepatitis C infection. Have known hypersensitivity or allergy to any components of the study vaccines (Anthrax Vaccine Adsorbed (AVA), CPG adjuvants, aluminum, benzethonium chloride [phemerol], formaldehyde). Have a history of receipt or plan to receive, while enrolled in this study, a licensed or unlicensed anthrax vaccine (except for the vaccines under study herein). Have a history of Potentially Immune-Mediated Medical Conditions (PIMMCs).* *Adverse Events of Special Interest Have a history of alcohol or drug abuse within 5 years prior to study enrollment or test positive on the screening urine test for drugs of abuse. Have any diagnosis, current or past, of schizophrenia, bipolar disease, or other psychiatric diagnosis that may interfere* with participant compliance or safety evaluations. *As determined by the site PI or appropriate sub-investigator. Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement for danger to self or others within 5 years prior to study vaccination. Received or plan to receive a licensed, live vaccine within 30 days before or after each study vaccination. Received or plan to receive a licensed, inactivated vaccine within 14 days before or after each study vaccination. Have a known history of documented anthrax disease or suspected exposure to anthrax. Received immunoglobulin or other blood products, except Rho(D) immunoglobulin, within 90 days prior to study vaccination. Received an experimental agent* within 30 days prior to the study vaccination or expect to receive another experimental agent** during the trial-reporting period.*** Including vaccine, drug, biologic, device, blood product, or medication. Other than from participation in this trial. ***Approximately 12 months after the second study vaccination. Are participating or plan to participate in another clinical trial with an interventional agent* that will be received during the trial-reporting period.** *Including licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication. **Approximately 12 months after the second study vaccination. Female participants who are breastfeeding or plan to breastfeed from the time of the first study vaccination through 30 days after the second study vaccination. Planning to donate blood within 4 months following second vaccination. Planned elective surgery during study participation. Member or immediate family member of the site research staff found on the delegation log. Previously served in the military any time after 1990 and/or plan to enlist in the military at any time during the study.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>AV7909 liquid formulation will be administered 0.5mL intramuscularly in a 2-dose schedule, 2 weeks apart (on Day 1 and Day 15). N=20 | Biological: AV7909<br>* AV7909 (Liquid Formulation) is an investigational vaccine that is a preformulated, sterile, milky-white suspension for IM injection. It consists of the Anthrax Vaccine Adsorbed (AVA) bulk drug substance and CPG 7909 adjuvant<br>|
| Active Comparator: Group 2<br>AV7909 lyophilized formulation will be administered 0.5mL intramuscularly in a 2-dose schedule, 2 weeks apart (on Day 1 and Day 15). N=20 | Biological: AV7909<br>* AV7909 (Lyophilized Formulation) is a thermostable, lyophilized version of the liquid AV7909 formulation. Sterile, milky-white suspension for intramuscular injection. It consists of polysorbate 80, CPG7909 adjuvant and AVA bulk drug substance<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of all Adverse Events of Special Interest (AESIs) | AESIs include all Potentially Immune Mediated Medical Conditions (PIMMCs). | Day 1 through Day 380 | 
| Occurrence of all Medically-Attended Adverse Events (MAAEs) | An MAAE is defined as an adverse event requiring unscheduled medical attention, such as: hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel for any reason. | Day 1 through Day 380 | 
| Occurrence of all Serious Adverse Events (SAEs) |  | Day 1 through Day 380 | 
| Occurrence of clinical safety laboratory Adverse Events (AEs) |  | Day 29 | 
| Occurrence of solicited injection site reactogenicity events |  | Day 1 through Day 22 | 
| Occurrence of solicited systemic reactogenicity events |  | Day 1 through Day 22 | 
| Occurrence of unsolicited non-serious adverse events |  | Day 1 through Day 64 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric mean titer (with 95% confidence interval) of anti-protective antigen (PA) immunoglobulin G (IgG) antibodies | Anti-PA IgG antibodies assessed by enzyme-linked immunosorbent assay (ELISA). | Day 1 through Day 380 | 
| Geometric mean titer (with 95% confidence interval) of toxin neutralizing antibodies | Antibodies assayed by toxin neutralization assay (50% effective dilution [ED50] and 50% neutralization factor [NF50]) in each study group compared with baseline (before vaccination). | Day 1 through Day 380 | 
| Proportion (with 95% confidence interval) of participants with putative seroprotection | Seroprotection is defined as 50% neutralization factor (NF50) >/= 0.56. | Day 1 through Day 380 | 
| Proportion (with 95% confidence interval) of participants with seroconversion by ELISA for antibodies | Seroconversion is defined as a >/=4-fold increase over baseline levels, or a >/=4-fold increase over the lower limit of quantification [LLOQ] if the baseline value is < LLOQ) | Day 1 through Day 380 | 
| Proportion (with 95% confidence interval) of participants with seroconversion by Toxin Neutralization Assay (TNA) for antibodies | Seroconversion is defined as a >/=4-fold increase over baseline levels, or a >/=4-fold increase over the lower limit of quantification [LLOQ] if the baseline value is < LLOQ) | Day 1 through Day 380 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anthrax, AV7909 (Liquid), Healthy Adult Volunteers, Immunogenicity, Phase 1, Safety, Thermostable AV7909 (Lyophilized), Vaccine