A Non-inferiority Trial to Compare MVA-BN® Smallpox Vaccine to ACAM2000®

Study Overview
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Brief Summary
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To demonstrate the efficacy of MVA-BN® in terms of vaccinia-specific Plaque Reduction Neutralization Test (PRNT) antibody response and by showing that vaccination prior to administration of ACAM2000® results in an attenuated take.

Detailed Description
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To demonstrate the efficacy of MVA-BN® by assessing non-inferiority of MVA-BN® compared to ACAM2000® in terms of vaccinia-specific Plaque Reduction Neutralization Test (PRNT) antibody response at the Peak Visits (Day 42 for Group 1 and Day 28 for Group 2) and by showing that vaccination with MVA-BN® prior to administration of ACAM2000® results in an attenuation of take.

Official Title
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A Randomized, Open-label Phase III Non-inferiority Trial to Compare Indicators of Efficacy for MVA-BN® Smallpox Vaccine to ACAM2000® in 18-42 Year Old Healthy Vaccinia-naïve Subjects

Conditions
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18-42 Year Old Healthy Vaccinia-naïve Subjects

Intervention / Treatment
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* Biological: MVA BN®
* Biological: ACAM2000®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and female subjects, 18-42 years of age The subject has read, signed and dated the Informed Consent, 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 procedure Acceptable medical history by screening evaluation and physical examination BMI greater or eaqual than 18.5 and smaller than 35 Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at Screening and a negative urine or serum pregnancy test within 24 hours prior to each vaccination WOCBP must have used an acceptable method of contraception for 28 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 surgically sterilized. (Acceptable contraception methods are restricted to abstinence, barrier contraceptives, intrauterine contraceptive devices or licensed hormonal products) Human Immunodeficiency Virus (HIV) antibody negative, hepatitis B surface antigen negative and negative antibody test to hepatitis C virus White blood cells greater or eaqual than 2500/mm3 and smaller than 11,000/mm3 Hemoglobin within normal limits Platelets greater or eaqual than lower normal limits Adequate renal function defined as a calculated Creatinine Clearance (CrCl) greater than 60 ml/min as estimated by the Cockcroft-Gault equation Adequate hepatic function in the absence of other evidence of significant liver disease defined as: Total bilirubin greater than 1.5 x Upper Limit Normal (ULN) Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) greater than 1.5 x ULN Alkaline Phosphatase (Alk Phos) greater than 1.5 x ULN Troponin I smaller than 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, atrioventricular 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: Pregnant or breast-feeding women Typical vaccinia scar Known or suspected history of smallpox vaccination defined as visible vaccination scar or documentation of smallpox vaccination or as reported by the subject History of vaccination with any poxvirus-based vaccine History of any serious medical condition, which in the opinion of the investigator would compromise the safety of the subject History of or active immunodeficiency or immunosuppression caused by acquired or congenital diseases or caused by ongoing treatments such as chronic (greater than 14 days) high-dose corticosteroids (smaller than 5 mg prednisone [or equivalent] per day applied systemically, i.e. parenterally or orally), chronic or planned treatment with steroid eye drops or ointment at time of enrollment or radiation, or immunosuppressive drugs; low-dose corticosteroid topical products and nasal sprays used sporadically, i.e. pro re nata (according to circumstances) are permissible Having had radiation or X-ray treatment (not routine X-rays) within the last 3 months Post organ and bone-marrow transplant subjects whether or not receiving chronic immunosuppressive therapy Eye surgery within 4 weeks prior to trial vaccination History of or active autoimmune disease. Persons with vitiligo or thyroid disease taking thyroid hormone replacement are not excluded Uncontrolled serious infection, i.e. not responding to antimicrobial therapy History of malignancy, other than squamous cell or basal cell skin cancer, unless there has been surgical excision considered to have achieved cure. Subjects with history of skin cancer must not be vaccinated at the previous site of cancer History of keloid formation History or clinical manifestation of severe hematological, renal, hepatic, pulmonary, central nervous, cardiovascular or gastrointestinal disorders History of coronary heart disease, myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, uncontrolled high blood pressure, or any other heart condition under the care of a doctor Chest pain (that is diagnosed as cardiac related) or trouble breathing on exertion 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 NOTE: This criterion applies only to subjects 20 years of age and older History of an immediate family member (father, mother, brother, or sister) who has had onset of ischemic heart disease before the age of 50 years Clinically significant psychological disorder not adequately controlled by medical treatment Active or history of chronic alcohol abuse and/or intravenous and/or nasal drug abuse (within the past 6 months) History of anaphylaxis or any severe allergic reaction or serious adverse reaction to a vaccine Eczema of any degree or history of eczema People with active atopic dermatitis (AD) [characterized by pruritus, eczematous lesions, xerosis (dry skin), and lichenification (thickening of the skin and an increase in skin markings] or with a history of AD People with chronic exfoliative skin disorders/conditions People with active current Varicella zoster, Herpes zoster, impetigo, uncontrolled acne, Darier's disease or any acute skin disorders of large magnitude, e.g., laceration requiring sutures People with a tattoo that covers the vaccination injection area (preventing assessment of the area and interfering with a vaccination site photograph) Having received any vaccinations or planned vaccinations with a live vaccine within 28 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 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 trial conclusion Use of any investigational or non-registered drug or vaccine other than the trial vaccines within 28 days preceding the first dose of the trial vaccine or planned administration of such a drug /vaccine during the trial period Blood donation for the duration of the trial Acute disease (illness with or without a fever) at the time of enrollment Temperature ≥ 100.4°F (38.0°C) at the time of enrollment Known household contacts with, or occupational exposure (other than minimal contact) to any of the following: Pregnant women Children <12 months of age People with eczema or a history of eczema People with active AD or history of AD People with chronic exfoliative skin disorders/conditions People with active Varicella zoster, Herpes zoster, impetigo, uncontrolled acne, Darier's disease or any acute skin disorders of large magnitude, e.g., laceration requiring sutures, burn with areas greater than 2×2 cm People with active or recent immunodeficiency disease or use of immunosuppressive medications, for example: have or take medication for HIV, AIDS, leukemia, lymphoma, or chronic liver problem, have or take medication for Crohn's disease, lupus, arthritis, or other immune disease; have had radiation or X-ray treatment (not routine X-rays) within the last 3 months; have ever had a bone-marrow or organ transplant (or take medication for that ); or have another problem that requires steroids, prednisone or a cancer drug for treatment People having had eye surgery within the last 4 weeks Known allergy to MVA-BN® vaccine or any of its constituents, e.g. tris(hydroxymethyl)-amino methane, including known allergy to egg or aminoglycoside (gentamycin) Known allergies to ACAM2000® and its diluents including polymyxin B sulfate, neomycin sulfate, and phenol Known allergies to vaccinia immunoglobulin (VIG) including thimerosal or previous allergic reaction to immunoglobulins Known allergies to cidofovir, sulfa drugs, or probenecid Trial personnel

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 42 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Two vaccinations; MVA BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA BN® vaccination (Day 56). | Biological: MVA BN®<br>* 0.5 ml MVA BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection<br>* Other names: IMVANEX;Biological: ACAM2000®<br>* 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.<br>|
| Active Comparator: Group 2<br>A single vaccination of ACAM2000® will be administered at Day 0. | Biological: ACAM2000®<br>* 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plaque Reduction Neutralization Test (PRNT) Geometric Mean Titer (GMT) at the Peak Visits | GMT based on vaccinia-specific PRNT. Titers below the detection limit are included with a value of 1. | Day 42 for Group 1 and Day 28 for Group 2 | 
| Maximum Lesion Area (MLA) in mm2 After Scarification With ACAM2000® | The MLA was defined as the maximum of two measurements: the lesion area measured on Day 6-8 (after scarification) or the lesion area measured on Day 13-15 (after scarification). This was measured using the SilhouetteConnect camera system, and confirmed by the Independent Take Review Committee (ITRC). | Day 6-8, 13-15 after 3rd Vaccination for Group 1 and Day 6-8, 13-15 after 1st vaccination for Group 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-measured Maximum Lesion Diameter (MLD) in mm After Scarification With ACAM2000 | The MLD was defined as the largest major diameter measured across the lesion on Day 6-8 (after scarification) or Day 13-15 (after scarification) | Day 6-8 and Day 13-15 after ACAM2000 scarification | 
| Investigator-measured Lesion Diameter in mm at Day 6-8 After Scarification With ACAM2000 | The lesion diameter at Day 6-8 was defined as the major lesion diameter measured on Day 6-8 (after scarification) | Day 6-8 after ACAM2000 scarification | 
| Investigator-measured Lesion Diameter in mm at Day 13-15 After Scarification With ACAM2000 | The lesion diameter at Day 13-15 was defined as the major lesion diameter measured on Day 13-15 (after scarification) | Day 13-15 after ACAM2000 scarification | 
| Individual Take as Classified by a Blinded Independent Take Review Committee (ITRC) | Take was assessed as either full, partial, or absent take by the ITRC based on Day 6-8 evaluations following ACAM2000 vaccination using subject profiles that contained supportive data up to Day 14 following ACAM2000 vaccination (in accordance with the ITRC Charter). | Day 6-8 visit following ACAM2000 vaccination | 
| Lesion Area in mm2 at Day 6-8 After Scarification With ACAM2000 | Lesion area was measured by the Investigator using the SilhouetteConnect camera system and confirmed by the blinded ITRC. | Day 6-8 after ACAM2000 scarification | 
| Lesion Area in mm2 at Day 13-15 After Scarification With ACAM2000 | Lesion area was measured by the Investigator using the SilhouetteConnect camera system and confirmed by the blinded ITRC. | Day 13-15 after ACAM2000 scarification | 
| Relationship to Vaccine of Any Serious Adverse Event (SAE) | Presentation of SAEs by relationship to study vaccine | Within 38 weeks for Group 1 and 30 weeks for Group 2 | 
| Intensity of Any Serious Adverse Event (SAE) | Presentation of SAEs by intensity | Within 38 weeks for Group 1 and 30 weeks for Group 2 | 
| Incidence of Any Cardiac Sign or Symptom Indicating a Case of Myo-/Pericarditis, i.e. Adverse Events of Special Interest (AESIs) | In this clinical trial, an AESI was defined as any cardiac sign or symptom developed since the first vaccination, any ECG changes determined to be clinically significant, or any cardiac enzyme results of Troponin I ≥ 2 x ULN. | Within 38 weeks for Group 1 and 30 weeks for Group 2 | 
| Related Grade >=3 Adverse Events | Incidence of any Grade 3 or 4 adverse events (AEs) possibly, probably, or definitely related to the vaccine. Pooled solicited (general only) and unsolicited AEs. | within 29 days after vaccination | 
| Relationship to Vaccine of Any Non-serious AEs | Presentation of non-serious AEs by relationship to study vaccine | within 29 days after vaccination | 
| Intensity of Any Non-serious AEs | Presentation of non-serious AEs by intensity | within 29 days after vaccination | 
| Solicited General AEs | Occurrence, intensity and relationship of solicited general AEs (body temperature [fever], headache, myalgia [muscle pain], chills, nausea, fatigue, malaise) | within 15 days after vaccination | 
| Incidence of Lymphadenopathy | Incidence of events of Lymphadenopathy. Pooled solicited and unsolicited events. | within 29 days after vaccination | 
| Solicited Local AEs: Intensity | Incidence of solicited local AEs (pain, redness [erythema], swelling, induration, itching [pruritus]) | within 15 days after vaccination | 
| Major Lesion Size, Major Erythema, and Major Induration Diameter | Daily measurement of major lesion size, major erythema, and major induration diameter (mm) based on physical appearance of vaccination site as documented in the memory aid. If the shape of the lesion, erythema [excludes lymphangitis], and induration observed was not round but rather asymmetrical, then the largest [or major] cross-sectional measurement was recorded. | Within 15 days after scarification with ACAM2000 | 
| GMTs at the Peak Visits and Individual Peak Measured by Vaccinia-specific ELISA | Peak Visit was defined as Day 42 for Group 1 and Day 28 for Group 2. Individual Peak was the maximum titer per subject from Visit 1 to Visit 7 (Week 8) in Group 1 and maximum titer from Visit 1 to Visit 6 (Week 8) in Group 2. Titers below the detection limit are included with a value of 1. | within 8 weeks (for both groups) | 
| GMTs at the Individual Peak Measured by Vaccinia-specific PRNT | Individual Peak was the maximum titer per subject from Visit 1 to Visit 7 (Week 8) in Group 1 and maximum titer from Visit 1 to Visit 6 (Week 8) in Group 2. Titers below the detection limit are included with a value of 1. | within 8 weeks (for both groups) | 
| GMTs as Measured by Vaccinia-specific ELISA | GMT based on vaccinia-specific ELISA. Titers below the detection limit are included with a value of '1'. | within 12 weeks | 
| GMTs as Measured by Vaccinia-specific PRNT | GMT based on vaccinia-specific PRNT. Titers below the detection limit are included with a value of '1'. | within 12 weeks | 
| PRNT Seroconversion Rates at Peak Visits | Seroconversion rate based on PRNT. Seroconversion is defined as the appearance of antibody titers greater than or equal 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. | Group 1 at Week 6; Group 2 at Week 4 | 
| ELISA Seroconversion Rates at Peak Visits | Seroconversion rate based on ELISA. Seroconversion is defined as the appearance of antibody titers greater than or equal 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. | Group 1 at Week 6; Group 2 at Week 4 |