A Phase II Trial to Compare a Liquid-frozen and a Freeze-dried Formulation of IMVAMUNE (MVA-BN®) Smallpox Vaccine in Vaccinia-naïve Healthy Subjects

Study Overview
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Brief Summary
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A randomized, double-blind, multicenter Phase II trial to compare the immunogenicity and safety of a liquid-frozen and a freeze-dried formulation of IMVAMUNE (MVA-BN®) smallpox vaccine in vaccinia-naïve healthy subjects

Official Title
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A Randomized, Double-blind, Multicenter Phase II Trial to Compare the Immunogenicity and Safety of a Liquid-frozen and a Freeze-dried Formulation of IMVAMUNE® (MVA-BN®) Smallpox Vaccine in Vaccinia-naïve Healthy Subjects

Conditions
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Smallpox

Intervention / Treatment
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* Biological: LF formulation of IMVAMUNE®
* Biological: FD formulation of IMVAMUNE®


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Male and female subjects, 18-55 years of age The subject has read, signed and dated 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 and has signed the Health Insurance Portability and Accountability Act (HIPAA) authorization form Body Mass Index (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 (SCR) and a negative urine pregnancy test within 24 hours prior to each vaccination White blood cells ≥ 2500/mm3 and < 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: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) in the absence of other evidence of significant liver disease 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 (PVC) 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 before 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 in the opinion of the investigator History of or active autoimmune disease, persons with vitiligo or thyroid disease taking thyroid hormone replacement are not excluded Known or suspected impairment of immunologic function including, but not limited to, clinically significant liver disease, 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, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, uncontrolled high blood pressure, or any other heart condition under the care of a doctor 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 Twenty 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 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 known allergy to egg or aminoglycoside (gentamycin) History of anaphylaxis or severe allergic reaction to any vaccine Acute disease (illness with or without a fever) at the time of 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 or after trial vaccination Having received any vaccinations or planned vaccinations with a killed vaccine within 14 days prior 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 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 (with the day of the FU call being considered the last day of the trial period). Trial personnel

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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>LF formulation of IMVAMUNE® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart | Biological: LF formulation of IMVAMUNE®<br> <br> |
| Experimental: Group 2<br>FD formulation of IMVAMUNE® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart | Biological: FD formulation of IMVAMUNE®<br> <br> |

What is the study measuring?
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Primary 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' | Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious Adverse Events | Occurrence, relationship to the trial vaccine and intensity of any Serious Adverse Event (SAE). | up to 32 weeks | 
| Number of Participants With Adverse Events of Special Interest (AESI) | Occurrence, relationship to the trial vaccine and intensity of any Adverse Event of Special Interest (AESI). AESIs were defined as any cardiac symptoms and ECG changes determined to be clinically significant or cardiac enzyme troponin I elevated above 2 x the Upper Limit of Normal | up to 32 weeks | 
| Number of Participants With Related Grade >=3 Adverse Events | Occurrence of any Grade >=3 Adverse Events related to the trial vaccine. | within 29 days after vaccination | 
| Number of Participants With Unsolicited Adverse Events | Occurrence, relationship to the trial vaccine and intensity of unsolicited treatment-emergent AEs (TEAEs). | within 29 days after vaccination | 
| Number of Participants With Solicited Local Averse Events | Occurrence and intensity of solicited local AEs (redness, swelling, induration, pruritus and pain) during the 8-day period (day of vaccination and the following 7 days) after any vaccination. Events were graded by intensity (1 = mild, 2 = moderate, 3 = severe). | 8 days after any vaccination | 
| Number of Participants With Solicited General Adverse Events | Occurrence, intensity and relationship to the trial vaccines of solicited general AEs (pyrexia, headache, myalgia, nausea, fatigue and chills) during the 8-day period (day of vaccination and the following 7 days) after any vaccination. Events were graded by intensity (1 = mild, 2 = moderate, 3 = severe). | within 8 days after any vaccination | 
| ELISA GMTs | Geometric Mean Titers (GMT) at all immunogenicity sampling time points based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). For the calculation of GMTs all measurements are included as they provide meaningful information even if below the detection limit (DL). Disregarding these measurements would highly bias the reported GMTs. We imputed values <DL as a value of '1' and the GMT and corresponding 95% confidence intervals were calculated. | within 8 weeks | 
| 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' | Week 6 | 
| PRNT GMTs | Geometric Mean Titers (GMT) at all immunogenicity sampling time points based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). For the calculation of GMTs all measurements are included as they provide meaningful information even if below the detection limit (DL). Disregarding these measurements would highly bias the reported GMTs. We imputed values <DL as a value of '1' and the GMT and corresponding 95% confidence intervals were calculated. | within 8 weeks | 
| Percentage of Participants With Seroconversion by ELISA | Seroconversion rate based on vaccinia-specific 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. | Week 6 | 
| Percentage of Participants With Seroconversion by ELISA | Seroconversion rates at all post-baseline immunogenicity sampling time points based on vaccinia-specific 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. | within 8 weeks | 
| Percentage of Participants With Seroconversion by PRNT | Seroconversion rate based on vaccinia-specific 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. | Week 6 | 
| Percentage of Participants With Seroconversion by PRNT | Seroconversion rates at all post-baseline immunogenicity sampling time points based on vaccinia-specific 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. | within 8 weeks | 
| ELISPOT Magnitudes of Response | Magnitudes of response of IFNγ producing T-cells measured by vaccinica-specific ELISPOT. Spot Forming Units below the detection limit are included as a value of '1'. | within 8 weeks | 
| Percentage of Participants With Response by ELISPOT | Response rates regarding IFNγ producing T-cells measured by vaccinia-specific ELISPOT. A response to the vaccine was defined as either the appearance of a positive signal for participants without a positive signal at Baseline or an increase by a factor of at least 1.7 of the SFU/1 x 10E6 PBMC compared to the Baseline SFU/1 x 10E6 PBMC for participants with a positive signal at Baseline. | within 8 weeks | 
| Percentage of Responders by ELISPOT | Responder rate measured by vaccinia specific ELISPOT. A participant was defined as a responder to the vaccine determined by ELISPOT if the participant had at least 1 post-baseline visit determined to be a response. A response to the vaccine was defined as either the appearance of a positive signal for participants without a positive signal at Baseline or an increase by a factor of at least 1.7 of the SFU/1 x 10E6 PBMC compared to the Baseline SFU/1 x 10E6 PBMC for participants with a positive signal at Baseline. | within 8 weeks | 
| Correlation ELISA vs PRNT Titers | Pearson Correlation Coefficient between the ELISA titers and the PRNT titers at weeks 4, 6 and 8 based on the log10 transformed titer values | within 8 weeks |