Freeze-Dried MVA-BN® Lot Consistency Smallpox Trial

Study Overview
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Brief Summary
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This is a Phase 3 multicenter trial to evaluate safety and immune response of three consecutive production lots of freeze-dried (FD) MVA-BN smallpox vaccine. The vaccine will be given to healthy subjects who do not have a smallpox scar. Approximately 1110 subjects will be randomly enrolled into one of three groups: Group 1 will include 370 subjects, who will receive two separate injections (shot) with a short needle, given below the skin of the upper arm with 0.5 mL FD MVA-BN (Lot 1). Group 2 will include 370 subjects, who will receive two separate injections (shot) with a short needle, given below the skin of the upper arm with 0.5 mL FD MVA-BN (Lot 2). Group 3 will include 370 subjects, who will receive two separate injections (shot) with a short needle, given below the skin of the upper arm with 0.5 mL FD MVA-BN (Lot 3). The primary objective of the trial is to show that the immune response elicited (produced) by three consecutively produced MVA-BN lots are statistically (numerically) comparable.

Official Title
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A Randomized, Double-blind, Multicenter Phase III Trial to Evaluate Immunogenicity and Safety of Three Consecutive Production Lots of a Freeze-dried Formulation of MVA-BN® Smallpox Vaccine in Healthy, Vaccinia-naïve Subjects

Conditions
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Smallpox

Intervention / Treatment
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* Biological: FD MVA-BN


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject has read, signed and dated the ICF Body Mass Index ≥ 18.5 and < 35 Women of childbearing potential (WOCBP) must have used an acceptable method of contraception for 30 days prior to the first vaccination, must agree to use an acceptable method of contraception during the trial, and must avoid becoming pregnant for at least 28 days after the last vaccination. A woman is considered of childbearing potential unless post-menopausal (defined as ≥ 12 months without a menstrual period) or surgically sterilized. Acceptable contraception methods are restricted to abstinence, barrier contraceptives, intrauterine contraceptive devices or licensed hormonal products). WOCBP must have a negative serum pregnancy test at screening (please note: a negative urine pregnancy test is required within 24 hours prior to each vaccination) White blood cells ≥ 2500/mm3 < ULN (Upper Limit of Normal) Absolute neutrophil count (ANC) within normal limits Hemoglobin within normal limits Platelets within normal limits Adequate renal function defined as a calculated Creatinine Clearance (CrCl) > 60 mL/min as estimated by the Cockcroft-Gault equation: (140 - age in years) x (body weight in kg) ÷ (serum creatinine in mg/dL x 72) = CrCl (mL/min). For women the result, calculated with the above formula, has to be multiplied by 0.85 = CrCl (mL/min) Adequate hepatic function defined as: Total bilirubin ≤ 1.5 x ULN in the absence of other evidence of significant liver disease Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase ≤ 1.5 x ULN Electrocardiogram (ECG) without clinically significant findings (e.g. any kind of atrioventricular or intraventricular conditions or blocks such as complete left or right bundle branch block, AV node block, QTc or PR prolongation, premature atrial contractions or other atrial arrhythmia, sustained ventricular arrhythmia, two premature ventricular contractions in a row, ST elevation consistent with ischemia). Exclusion Criteria: Typical vaccinia scar Known or suspected history of smallpox vaccination History of vaccination with any poxvirus-based vaccine US Military service prior to 1991 or after January 2003 Pregnant or breast-feeding women Uncontrolled serious infection, i.e. not responding to antimicrobial therapy History of any serious medical condition, which in the opinion of the investigator would compromise the safety of the subject or would limit the subject's ability to complete the trial History of or active autoimmune disease, persons with vitiligo or thyroid disease taking thyroid replacement are not excluded Known or suspected impairment of immunologic function including, but not limited to, human immunodeficiency virus (HIV) Infection, clinically significant liver disease (including chronic active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection), diabetes mellitus History of malignancy other than squamous cell or basal cell skin cancer, unless there has been surgical excision that is considered to have achieved cure. Subjects with history of skin cancer must not be vaccinated at the previous tumor site. History or clinical manifestation of clinically significant and severe hematological, pulmonary, central nervous, cardiovascular or gastrointestinal disorders Clinically significant mental disorder not adequately controlled by medical treatment History of coronary heart disease, myocardial infarction, angina pectoris, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, uncontrolled high blood pressure, or any other heart condition under the care of a doctor Abnormal Troponin I level > ULN Known history of an immediate family member (father, mother, brother, or sister) who has had onset of ischemic heart disease before age 50 years Active or history of chronic alcohol abuse and/or intravenous and/or nasal drug abuse (within the past 6 months) Known allergy to MVA-BN vaccine or any of its constituents, e.g. tris (hydroxymethyl)-amino methane, including known allergy to egg or aminoglycosides History of anaphylaxis or severe allergic reaction to any vaccine Acute disease (illness with or without a fever) at the time enrollment Body temperature ≥ 100.4°F (≥ 38.0°C) at the time of enrollment Having received any vaccinations or planned vaccinations with a live vaccine within 30 days prior to or after trial vaccination Having received any vaccinations or planned vaccinations with a killed/inactivated vaccine within 14 days prior to or after trial vaccination Chronic systemic administration (defined as more than 14 days) of > 5 mg prednisone (or equivalent)/day or any other immune-modifying drugs during a period starting from three months prior to administration of the vaccine and ending at last physical trial visit (Visit 5) Post organ transplant subjects whether or not receiving chronic immunosuppressive therapy Administration or planned administration of immunoglobulins and/or any blood products during a period starting from three months prior to administration of the vaccine and ending at last physical trial visit (Visit 5) Use of any investigational or non-registered product within 30 days preceding the first dose of the trial vaccine, or planned administration of such a drug during the trial period Trial personnel

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 |
| --- | --- |
| Active Comparator: GP 1: two doses of FD MVA-BN--Lot 1<br>Healthy, vaccinia-naïve subjects receiving two subcutaneous (SC) vaccinations, four weeks apart with freeze-dried (FD) MVA-BN® - Lot 1 | Biological: FD MVA-BN<br>* Vaccinations with a 0.5 mL dose of vaccine containing at least 0.5 x 10E8 Infectious Units (Inf.U)<br>|
| Active Comparator: GP 2: two doses of FD MVA-BN--Lot 2<br>Healthy, vaccinia-naïve subjects receiving two subcutaneous (SC) vaccinations, four weeks apart with freeze-dried (FD) MVA-BN® - Lot 2 | Biological: FD MVA-BN<br>* Vaccinations with a 0.5 mL dose of vaccine containing at least 0.5 x 10E8 Infectious Units (Inf.U)<br>|
| Active Comparator: GP 3: two doses of FD MVA-BN--Lot 3<br>Healthy, vaccinia-naïve subjects receiving two subcutaneous (SC) vaccinations, four weeks apart with freeze-dried (FD) MVA-BN® - Lot 3 | Biological: FD MVA-BN<br>* Vaccinations with a 0.5 mL dose of vaccine containing at least 0.5 x 10E8 Infectious Units (Inf.U)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaccinia-Specific Neutralizing Antibodies Measured by Plaque Reduction Neutralization Test (PRNT) | Vaccinia-specific neutralizing antibody titers below the lower limit of quantitation are given a value 10, i.e., half of the PRNT lower limit of quantitation of 20. | Two weeks post second vaccination; approximately Week 6. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaccinia-Specific Total Antibodies Measured by Enzyme-Linked Immunosorbant Assay (ELISA) | Vaccinia-specific total antibody titers below the lower limit of quantitation are given a value 100, i.e., half of the ELISA lower limit of quantitation of 200. | Two weeks post second vaccination; approximately Week 6. | 
| Seroconversion Rates for Vaccinia-Specific Neutralizing Antibodies by PRNT | Seroconversion is defined as either the appearance of antibody titers >= LLOQ for subjects with a titer below LLOQ at baseline, or a doubling (or more) of the antibody titer compared to the baseline titer for subjects with a titer equal or above the LLOQ at baseline. The LLOQ for PRNT is 20. | Two weeks post second vaccination; approximately Week 6. | 
| Seroconversion Rates for Vaccinia-Specific Total Antibodies by ELISA | Seroconversion is defined as either the appearance of antibody titers >= LLOQ for subjects with a titer below LLOQ at baseline, or a doubling (or more) of the antibody titer compared to the baseline titer for subjects with a titer equal or above the LLOQ at baseline. The LLOQ for ELISA is 200. | Two weeks post second vaccination; approximately Week 6. | 
| Pearson Correlation Coefficient Between the log10 Transformed PRNT Titers and the log10 Transformed ELISA Titers | Pearson correlation coefficient calculated on the log10 PRNT vs. ELISA titers at 2 weeks post second vaccination. | Two weeks post second vaccination; approximately Week 6. | 
| Occurrence, Relationship and Intensity of Any Serious Adverse Event (SAE) at Any Time During the Trial | Occurrence is defined as the number of participants who experienced an SAE. Related SAEs are defined as those for which causality to trial vaccine was considered possible, probable, definite, or was missing. Intensity is defined per the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, published September 2007, where >= Grade 3 is either Severe or Potentially Life Threatening. | Overall study, ie from first vaccination at Visit 1 through the Follow-up Visit approximately 32 weeks post first vaccination. | 
| Occurrence, Relationship and Intensity of Any Cardiac Sign or Symptom Indicating a Case of Myo-/Pericarditis at Any Time During the Trial. | Occurrence is defined as the number of participants who experienced an event falling in the system organ class of Cardiac disorders per MedDRA version 22.0. Related cardiac signs and symptoms are defined as those for which causality to trial vaccine was considered possible, probable, definite, or was missing. Intensity is defined per the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, published September 2007, where >= Grade 3 is either Severe or Potentially Life Threatening. | Overall study, ie from first vaccination at Visit 1 through the Follow-up Visit approximately 32 weeks post first vaccination. | 
| Occurrence of Any Grade 3 or 4 Unsolicited AEs Probably, Possibly or Definitely Related to the Trial Vaccine | Related AEs are defined as those for which causality to trial vaccine was considered possible, probable, definite, or was missing. Intensity is defined per the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, published September 2007, where Grade 3 is Severe and Grade 4 is Potentially Life Threatening. | Within 28 days (and up to 35 days) after each vaccination, ie, from Visit 1 to Visit 3 for the first vaccination and from Visit 3 to Visit 5 for the second vaccination based on the protocol scheduled visits. | 
| Occurrence, Relationship and Intensity of Unsolicited AEs | Occurrence is defined as the number of participants who experienced an unsolicited AE. Related unsolicited AEs are defined as those for which causality to trial vaccine was considered possible, probable, definite, or was missing. Intensity is defined per the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, published September 2007, where >= Grade 3 is either Severe or Potentially Life Threatening. | Within 28 days (and up to 35 days) after each vaccination, ie, from Visit 1 to Visit 3 for the first vaccination and from Visit 3 to Visit 5 for the second vaccination based on the protocol scheduled visits. | 
| Occurrence and Intensity of Solicited Local AEs (Redness, Swelling, Induration, Pruritus and Pain). | Occurrence is defined as the number of participants who experienced a solicited local AE. Intensity is defined per the protocol for each local event type. For injection site erythema, swelling, and induration the intensity is graded based on the maximum diameter as Grade 1: < 30mm, Grade 2: >= 30 - < 100mm, Grade 3: >= 100mm. Intensity for pruritis is defined as Grade 1: mild, Grade 2: moderate, Grade 3: severe. Intensity for injection site pain is defined as Grade 1: Painful on touch, Grade 2: Painful when moving the limb, Grade 3: Spontaneously painful/prevents normal activity. If a participant experienced the local event after both vaccinations, the maximum intensity is presented. | During the 8 day period (day of vaccination and the following 7 days) after each vaccination, ie Days 1-8 for the first vaccination and Days 28-35 for the second vaccination based on the protocol scheduled visits. | 
| Duration of Solicited Local AEs (Redness, Swelling, Induration, Pruritus and Pain). | Number of days from the start of the local event to resolution. If a participant experienced the local event after both vaccinations, the longer duration is presented. Subjects who had a missing resolution date for the event are not included in the analysis. | Starting during the 8 day period (day of vaccination and the following 7 days) after each vaccination, ie, Days 1-8 for the first vaccination and Days 28-35 for the second vaccination based on the protocol scheduled visits, through resolution. | 
| Occurrence, Relationship, and Intensity of Solicited General AEs (Pyrexia, Headache, Myalgia, Nausea, Fatigue and Chills). | Occurrence is defined as the number of participants who experienced a solicited general AE. Related solicited general AEs are defined as those for which causality to trial vaccine was considered possible, probable, definite, or was missing. Intensity is defined per the protocol for each general event type. For pyrexia (increased body temperature) grading is defined as Grade 1: ≥ 99.5 - < 100.4°F (≥ 37.5 - < 38.0°C), Grade 2:≥ 100.4 - < 102.2°F (≥ 38.0 - < 39.0°C), Grade 3:≥ 102.2 - < 104°F (≥ 39.0 - < 40.0°C), and Grade 4: ≥ 104°F (≥ 40.0°C). Intensity for headache, myalgia, nausea, fatigue and chills is defined as Grade 1: mild, Grade 2: moderate, Grade 3: severe. If a participant experienced the general event after both vaccinations, the maximum intensity is presented. | During the 8 day period (day of vaccination and the following 7 days) after each vaccination, ie Days 1-8 for the first vaccination and Days 28-35 for the second vaccination based on the protocol scheduled visits. | 
| Duration of Solicited General AEs (Pyrexia [Body Temperature Increase], Headache, Myalgia, Nausea, Fatigue and Chills) | Number of days from the start of the general event to resolution. If a participant experienced the general event after both vaccinations, the longer duration is presented. Subjects who had a missing resolution date for the event are not included in the analysis. | Starting during the 8 day period (day of vaccination and the following 7 days) after each vaccination, ie, Days 1-8 for the first vaccination and Days 28-35 for the second vaccination based on the protocol scheduled visits, through resolution. |