A Trial to Evaluate Immunogenicity and Safety of Three Consecutive Production Lots of IMVAMUNE® (MVA-BN®) Smallpox Vaccine in Healthy, Vaccinia-naïve Subjects

Study Overview
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Brief Summary
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A randomized, double-blind, placebo-controlled Phase III trial to evaluate immunogenicity and safety of three consecutive production lots of IMVAMUNE® (MVA-BN®) smallpox vaccine in healthy, vaccinia-naïve subjects.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Phase III Trial to Evaluate Immunogenicity and Safety of Three Consecutive Production Lots of IMVAMUNE® (MVA-BN®) Smallpox Vaccine in Healthy, Vaccinia-Naïve Subjects

Conditions
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Smallpox

Intervention / Treatment
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* Biological: IMVAMUNE®
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects, 18 to 40 years of age The subject has read, signed and dated the informed consent form, having been advised of the risks and benefits of the trial in a language understood by the subject and prior to performance of any trial specific procedures BMI ≥ 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 or with a history of hysterectomy (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 and a negative urine pregnancy test within 24 hours prior to each vaccination White blood cells ≥ 2,500/mm3 < ULN 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: For men: (140 - age in years) x (body weight in kg) ÷ (serum creatinine in mg/dl x 72) = CrCl (ml/min) For women: multiply the result by 0.85 = CrCl (ml/min). Adequate hepatic function defined as: a. Total bilirubin ≤ 1.5 x ULN in the absence of other evidence of significant liver disease b. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase ≤ 1.5 x ULN Troponin I < 2 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, HIV Infection, clinically significant liver disease (including chronic active HBV or HCV), diabetes mellitus, moderate to severe kidney impairment 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 Known history of an immediate family member (father, mother, brother, or sister) who has had onset of ischemic heart disease before age 50 years Ten percent or greater risk of developing a myocardial infarction or coronary death within the next 10 years using the National Cholesterol Education Program's risk assessment tool (http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof) NOTE: This criterion applies only to subjects 20 years of age and older Active or history of chronic alcohol abuse and/or intravenous and/or nasal drug abuse (within the past 6 months) Known allergy to IMVAMUNE® vaccine and its constituents, e.g. tris (hydroxymethyl)-amino methane, including know 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 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 (V5) 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 (V5) Use of any investigational or non-registered drug or vaccine other than the trial vaccine 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: 40 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 |
| --- | --- |
| Experimental: Group 1<br>Two vaccinations four weeks apart (at Day 0 and Day 28) with IMVAMUNE® Lot #1 | Biological: IMVAMUNE®<br>* 0.5 ml IMVAMUNE® vaccine containing at least 1 x 10E8 TCID50 (standard dose)<br>* Other names: MVA-BN®;|
| Experimental: Group 2<br>Two vaccinations four weeks apart (at Day 0 and Day 28) with IMVAMUNE® Lot #2 | Biological: IMVAMUNE®<br>* 0.5 ml IMVAMUNE® vaccine containing at least 1 x 10E8 TCID50 (standard dose)<br>* Other names: MVA-BN®;|
| Experimental: Group 3<br>Two vaccinations four weeks apart (at Day 0 and Day 28) with IMVAMUNE® Lot #3 | Biological: IMVAMUNE®<br>* 0.5 ml IMVAMUNE® vaccine containing at least 1 x 10E8 TCID50 (standard dose)<br>* Other names: MVA-BN®;|
| Placebo Comparator: Group 4<br>Two vaccinations four weeks apart (at Day 0 and Day 28) with 0.5 ml Placebo, Tris-buffered saline (TBS) | Other: Placebo<br>* 0.5 ml TBS<br>* Other names: Tris-buffered-saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PRNT GMT | Geometric Mean Titers (GMT) based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Titers below the detection limit are included with a value of '1'. | 2 weeks following the second vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ELISA GMT | Geometric Mean Titers (GMT) based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Titers below the detection limit are included with a value of '1'. | 2 weeks following the second vaccination | 
| PRNT Seroconversion Rate | Seroconversion rate based on Plaque Reduction Neutralization Test (PRNT). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (2) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. Percentages based on number of subjects with data available. | 2 weeks following the second vaccination | 
| ELISA Seroconversion Rate | Seroconversion rate based on Enzyme-linked Immunosorbent Assay (ELISA). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (50) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. Percentages based on number of subjects with data available. | 2 weeks following the second vaccination | 
| Correlation PRNT vs ELISA Titers | Pearson Correlation Coefficient between the log10 transformed PRNT titers and the log10 transformed ELISA titers | 2 weeks following the second vaccination | 
| Serious Adverse Events | Incidence, relationship and intensity of any Serious Adverse Event (SAE) | within 30 weeks | 
| Cardiac Signs or Symptoms | Incidence, relationship and intensity of any cardiac sign or symptom indicating a case of myo-/pericarditis (Adverse Event of Special Interest (AESI)). An AESI was defined in this trial as: Any cardiac sign or symptom developed since the first vaccination ECG changes determined to be clinically significant Cardiac enzyme Troponin I >= 2 x ULN (>= Grade 2) | within 30 weeks | 
| Related Grade >=3 Adverse Events | Incidence of any Grade >=3 Adverse Events probably, possibly or definitely related to the trial vaccine. Pooled solicited (general only) and unsolicited AEs | within 29 days after any vaccination | 
| Unsolicited Non-serious AEs: Intensity | Occurrence of unsolicited non-serious AEs by Intensity | within 29 days after any vaccination | 
| Unsolicited Non-serious AEs: Relationship to Vaccination | Occurrence of unsolicited non-serious AEs by relationship to study vaccine | within 29 days after any vaccination | 
| Solicited Local AEs | Incidence and intensity of solicited local AEs (redness, swelling, induration, pruritus and pain). Percentages based on subjects with at least one completed diary card. | within 8 days after any vaccination | 
| Solicited General AEs | Incidence of solicited general AEs (pyrexia, headache, myalgia, chills, nausea, and fatigue): Intensity and relationship to vaccination. Percentages based on subjects with at least one completed diary card. | within 8 days after any vaccination |