A Study to Evaluate Safety and Immunogenicity of One and Two Doses of IMVAMUNE® Smallpox Vaccine in 56-80 Year Old Vaccinia-experienced Subjects
Primary Purpose
Smallpox
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
IMVAMUNE
IMVAMUNE
Sponsored by
About this trial
This is an interventional prevention trial for Smallpox
Eligibility Criteria
Inclusion Criteria:
- Male and female subjects 56-70 years of age. If no safety concerns are identified upon review of the safety data from the first 30 subjects enrolled, the age range is extended up to 80 years.
- Time since most current smallpox vaccination > 10 years.
- The subject has read, signed and dated the Informed Consent Form (ICF), successfully completed (at least 90% correct [no more than 3 attempts allowed]) the test of understanding and has signed the Health Insurance Portability and Accountability Act (HIPAA) authorization form.
- Women must have a negative serum pregnancy test at screening and negative urine pregnancy test within 24 hours prior to vaccination.
- 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 study and must not plan to become pregnant for at least 28 days after the last vaccination. (Acceptable contraception methods are restricted to abstinence, barrier contraceptives, intrauterine contraceptive devices or licensed hormonal products).
- Weight: ≥ 100 pounds (45.5 kg) and ≤ 330 pounds (150 kg).
- White blood cells ≥ 2500/mm3 and < 11,000/mm3.
- Absolute neutrophil count within normal limits.
- Hemoglobin within normal limits.
- Platelets within normal limits.
Adequate renal function defined as:
- Urine protein ≤ +1 (by dip stick)
- Serum creatinine within normal limits
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.
- Cardiac 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, sustained atrial arrhythmias, sustained ventricular arrhythmia, 2 premature ventricular contractions (PVC) in a row, ST elevation consistent with ischemia.
Exclusion Criteria:
- History of or active immunodeficiency or immuno-suppression caused by acquired or congenital diseases or caused by treatments such as chronic administration (> 14 days) of systemic, i.e. parenteral or oral, corticosteroids (> 5 mg prednisone [or equivalent] per day), radiation or immune-modifying drugs.
- Periodic steroid injections, e.g. intraarticular, are not allowed within 30 days prior to the first vaccination and throughout the study until Visit 5 (V5).
- Post organ transplant subjects whether or not receiving chronic immunosuppressive therapy.
- 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 prevent the subject from complying with study requirements.
- History of or active autoimmune disease, e.g. Type I diabetes. Persons with vitiligo or thyroid disease taking thyroid hormone replacement are not excluded.
- Skin cancer in the past six months. If treatment for skin cancer was successfully completed more than six months ago and the malignancy is considered to be cured, the subject may be enrolled. Subjects with history of skin cancer must not be vaccinated at the previous site of cancer.
- Any other malignancy in the past five years. If treatment for cancer was successfully completed more than 5 years ago and the malignancy is considered to be cured, the subject may be enrolled.
- Clinically significant hematological, renal, hepatic, pulmonary, central nervous, cardiovascular or gastrointestinal disorders which are not adequately controlled by medical treatment within the last 12 weeks before vaccination as judged by the site's Principal Investigator.
- History of myocardial infarction, congestive heart failure with marked limitation of activity due to symptoms, e.g. walking short distances [20 100 m] (i.e. > Grade II according to the New York Heart Association), cardiomyopathy and stroke or transient ischemic attack in the past two years.
- Uncontrolled high blood pressure defined as systolic blood pressure ≥ 150 mm Hg and/or ≥ diastolic blood pressure ≥ 100 mm Hg within the last six months.
- Subjects with active coronary heart disease manifested by angina, even if on medication.
- 25 % 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
- Clinically significant mental disorder not adequately controlled by medical treatment.
- History of chronic alcohol abuse (40 g/day, e.g. 3 glasses of beer or 2 glasses of wine for at least six months) and/or intravenous drug abuse (within the last six months). Subjects with a history of other substance and/or alcohol abuse are also excluded if - in the opinion of the investigator - the abuse could prevent the subject from complying with study requirements.
- History of allergic disease or reactions likely to be exacerbated by IMVAMUNE® or any component of the vaccine, e.g. tris(hydroxymethyl)-amino methane, chicken embryo fibroblast proteins, aminoglycosides (gentamycin).
- History of anaphylactic shock or any severe allergic reaction to a vaccine requiring immediate treatment.
- Subjects undergoing treatment for tuberculosis infection or disease.
- Having received any vaccinations or planned vaccinations with a live vaccine within 30 days prior to or after study vaccination.
- Having received any vaccinations or planned vaccinations with a killed vaccine within 14 days prior to or after study vaccination.
- Administration or planned administration of immuno-globulins and/or any blood products during a period starting from three months prior to administration of the vaccine and ending at study conclusion.
- Use of any investigational or non-registered drug or vaccine other than the study vaccine within 30 days preceding the first dose of the study vaccine or planned administration of such a drug during the study period.
- Temperature ≥ 100.4°F (38.0°C) at the time of enrollment.
- Any condition which might interfere with study objectives or would limit the subject's ability to complete the study in the opinion of the investigator.
- Study personnel.
Sites / Locations
- Orlando Clinical Research Center
- University of Iowa
- University of Kentucky, School of Medicine, Department of Medicine
- University of Rochester, Medical Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Group 1
Group 2
Arm Description
Outcomes
Primary Outcome Measures
Related Serious Adverse Events
Incidence of Serious Adverse Events (SAEs) probably, possibly or definitely related to the trial vaccine
Secondary Outcome Measures
Unsolicited Non-serious AEs: Intensity
Occurrence of unsolicited non-serious AEs by Intensity
Unsolicited Non-serious AEs: Relationship to Vaccination
Occurrence of unsolicited non-serious AEs by relationship to study vaccine
Related Grade >=3 Adverse Events
Incidence of any Grade >=3 Adverse Events probably, possibly or definitely related to the trial vaccine. Pooled solicited (general) and unsolicited AEs
Cardiac Signs or Symptoms
Incidence, relationship and intensity of any cardiac sign or symptom indicating a case of myo-/pericarditis (AESI). AESIs were defined as any cardiac symptoms and ECG changes determined to be clinically significant or cardiac enzymes elevated above 2 x upper limit of normal range (ULN).
Solicited Local Adverse Events
Incidence and intensity of solicited local AEs (pain, erythema, swelling, induration, and pruritus). Percentages based on subjects with at least one completed diary card.
Solicited General Adverse Events
Incidence of solicited general AEs (body temperature increased, headache, myalgia, chills, nausea, and fatigue): Intensity and relationship tovaccination. Percentages based on subjects with at least one completed diary card.
ELISA Response Rate
Response rate based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Response is defined as the appearance of antibody titers ≥ detection limit (50) for initially seronegative subjects, or an increase of the antibody titer compared to Baseline titer for initially seropositive subjects. Individual peak response rate is based on the maximum post-Baseline antibody titer within 8 weeks (end of active trial phase). Percentages based on number of subjects with data available.
ELISA Seroconversion Rate
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. Individual peak seroconversion rate is based on the maximum post-Baseline antibody titer within 8 weeks (end of active trial phase). Percentages based on number of subjects with data available.
ELISA GMT
Geometric Mean Titers (GMT) based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Individual peak is defined as the maximum post-Baseline antibody titer within 8 weeks (end of active trial phase). Titers below the detection limit are included with a value of '1'.
PRNT Response Rate
Response rate based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Response is defined as the appearance of antibody titers ≥ detection limit (15) for initially seronegative subjects, or an increase of the antibody titer compared to Baseline titer for initially seropositive subjects. Individual peak response rate is based on the maximum post-Baseline antibody titer within 8 weeks (end of active trial phase). Percentages based on number of subjects with data available.
PRNT Seroconversion Rate
Seroconversion rate based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (15) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. Individual peak seroconversion rate is based on the maximum post-Baseline antibody titer within 8 weeks (end of active trial phase). Percentages based on number of subjects with data available.
PRNT GMT
Geometric Mean Titers (GMT) based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Individual peak is defined as the maximum post-Baseline antibody titer within 8 weeks (end of active trial phase). Titers below the detection limit are included with a value of '1'.
Correlation PRNT vs ELISA Titers
Pearson Correlation Coefficient between the log10 transformed PRNT titers and the log10 transformed ELISA titers
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00857493
Brief Title
A Study to Evaluate Safety and Immunogenicity of One and Two Doses of IMVAMUNE® Smallpox Vaccine in 56-80 Year Old Vaccinia-experienced Subjects
Official Title
A Randomized, Double-blind, Placebo-controlled Phase II Study to Evaluate Safety and Immunogenicity of One and Two Doses of IMVAMUNE® Smallpox Vaccine in 56-80 Year Old Vaccinia-experienced Subjects
Study Type
Interventional
2. Study Status
Record Verification Date
January 2019
Overall Recruitment Status
Completed
Study Start Date
June 2009 (undefined)
Primary Completion Date
August 2010 (Actual)
Study Completion Date
August 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bavarian Nordic
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
A Randomized, Double-Blind, Placebo-Controlled Phase II Study to Evaluate Safety and Immunogenicity of One and Two Doses of IMVAMUNE® Smallpox Vaccine in 56-80 Year Old Vaccinia-Experienced Subjects
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Smallpox
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
120 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Group 1
Arm Type
Experimental
Arm Title
Group 2
Arm Type
Experimental
Intervention Type
Biological
Intervention Name(s)
IMVAMUNE
Intervention Description
Two s.c. vaccinations with 0.5 ml IMVAMUNE® vaccine containing 1 x 10E8 TCID50 / dose
Intervention Type
Biological
Intervention Name(s)
IMVAMUNE
Intervention Description
One s.c. vaccination with placebo (0.5 ml saline), followed by a second s.c. vaccination with 0.5 ml IMVAMUNE® vaccine containing 1 x 10E8 TCID50
Primary Outcome Measure Information:
Title
Related Serious Adverse Events
Description
Incidence of Serious Adverse Events (SAEs) probably, possibly or definitely related to the trial vaccine
Time Frame
within 8 weeks
Secondary Outcome Measure Information:
Title
Unsolicited Non-serious AEs: Intensity
Description
Occurrence of unsolicited non-serious AEs by Intensity
Time Frame
within 29 days after any vaccination
Title
Unsolicited Non-serious AEs: Relationship to Vaccination
Description
Occurrence of unsolicited non-serious AEs by relationship to study vaccine
Time Frame
within 29 days after any vaccination
Title
Related Grade >=3 Adverse Events
Description
Incidence of any Grade >=3 Adverse Events probably, possibly or definitely related to the trial vaccine. Pooled solicited (general) and unsolicited AEs
Time Frame
within 29 days after any vaccination
Title
Cardiac Signs or Symptoms
Description
Incidence, relationship and intensity of any cardiac sign or symptom indicating a case of myo-/pericarditis (AESI). AESIs were defined as any cardiac symptoms and ECG changes determined to be clinically significant or cardiac enzymes elevated above 2 x upper limit of normal range (ULN).
Time Frame
within 32 weeks
Title
Solicited Local Adverse Events
Description
Incidence and intensity of solicited local AEs (pain, erythema, swelling, induration, and pruritus). Percentages based on subjects with at least one completed diary card.
Time Frame
within 8 days after any vaccination
Title
Solicited General Adverse Events
Description
Incidence of solicited general AEs (body temperature increased, headache, myalgia, chills, nausea, and fatigue): Intensity and relationship tovaccination. Percentages based on subjects with at least one completed diary card.
Time Frame
within 8 days after any vaccination
Title
ELISA Response Rate
Description
Response rate based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Response is defined as the appearance of antibody titers ≥ detection limit (50) for initially seronegative subjects, or an increase of the antibody titer compared to Baseline titer for initially seropositive subjects. Individual peak response rate is based on the maximum post-Baseline antibody titer within 8 weeks (end of active trial phase). Percentages based on number of subjects with data available.
Time Frame
within 32 weeks
Title
ELISA Seroconversion Rate
Description
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. Individual peak seroconversion rate is based on the maximum post-Baseline antibody titer within 8 weeks (end of active trial phase). Percentages based on number of subjects with data available.
Time Frame
within 32 weeks
Title
ELISA GMT
Description
Geometric Mean Titers (GMT) based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Individual peak is defined as the maximum post-Baseline antibody titer within 8 weeks (end of active trial phase). Titers below the detection limit are included with a value of '1'.
Time Frame
within 32 weeks
Title
PRNT Response Rate
Description
Response rate based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Response is defined as the appearance of antibody titers ≥ detection limit (15) for initially seronegative subjects, or an increase of the antibody titer compared to Baseline titer for initially seropositive subjects. Individual peak response rate is based on the maximum post-Baseline antibody titer within 8 weeks (end of active trial phase). Percentages based on number of subjects with data available.
Time Frame
within 32 weeks
Title
PRNT Seroconversion Rate
Description
Seroconversion rate based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (15) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. Individual peak seroconversion rate is based on the maximum post-Baseline antibody titer within 8 weeks (end of active trial phase). Percentages based on number of subjects with data available.
Time Frame
within 32 weeks
Title
PRNT GMT
Description
Geometric Mean Titers (GMT) based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Individual peak is defined as the maximum post-Baseline antibody titer within 8 weeks (end of active trial phase). Titers below the detection limit are included with a value of '1'.
Time Frame
within 32 weeks
Title
Correlation PRNT vs ELISA Titers
Description
Pearson Correlation Coefficient between the log10 transformed PRNT titers and the log10 transformed ELISA titers
Time Frame
within 32 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
56 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Male and female subjects 56-70 years of age. If no safety concerns are identified upon review of the safety data from the first 30 subjects enrolled, the age range is extended up to 80 years.
Time since most current smallpox vaccination > 10 years.
The subject has read, signed and dated the Informed Consent Form (ICF), successfully completed (at least 90% correct [no more than 3 attempts allowed]) the test of understanding and has signed the Health Insurance Portability and Accountability Act (HIPAA) authorization form.
Women must have a negative serum pregnancy test at screening and negative urine pregnancy test within 24 hours prior to vaccination.
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 study and must not plan to become pregnant for at least 28 days after the last vaccination. (Acceptable contraception methods are restricted to abstinence, barrier contraceptives, intrauterine contraceptive devices or licensed hormonal products).
Weight: ≥ 100 pounds (45.5 kg) and ≤ 330 pounds (150 kg).
White blood cells ≥ 2500/mm3 and < 11,000/mm3.
Absolute neutrophil count within normal limits.
Hemoglobin within normal limits.
Platelets within normal limits.
Adequate renal function defined as:
Urine protein ≤ +1 (by dip stick)
Serum creatinine within normal limits
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.
Cardiac 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, sustained atrial arrhythmias, sustained ventricular arrhythmia, 2 premature ventricular contractions (PVC) in a row, ST elevation consistent with ischemia.
Exclusion Criteria:
History of or active immunodeficiency or immuno-suppression caused by acquired or congenital diseases or caused by treatments such as chronic administration (> 14 days) of systemic, i.e. parenteral or oral, corticosteroids (> 5 mg prednisone [or equivalent] per day), radiation or immune-modifying drugs.
Periodic steroid injections, e.g. intraarticular, are not allowed within 30 days prior to the first vaccination and throughout the study until Visit 5 (V5).
Post organ transplant subjects whether or not receiving chronic immunosuppressive therapy.
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 prevent the subject from complying with study requirements.
History of or active autoimmune disease, e.g. Type I diabetes. Persons with vitiligo or thyroid disease taking thyroid hormone replacement are not excluded.
Skin cancer in the past six months. If treatment for skin cancer was successfully completed more than six months ago and the malignancy is considered to be cured, the subject may be enrolled. Subjects with history of skin cancer must not be vaccinated at the previous site of cancer.
Any other malignancy in the past five years. If treatment for cancer was successfully completed more than 5 years ago and the malignancy is considered to be cured, the subject may be enrolled.
Clinically significant hematological, renal, hepatic, pulmonary, central nervous, cardiovascular or gastrointestinal disorders which are not adequately controlled by medical treatment within the last 12 weeks before vaccination as judged by the site's Principal Investigator.
History of myocardial infarction, congestive heart failure with marked limitation of activity due to symptoms, e.g. walking short distances [20 100 m] (i.e. > Grade II according to the New York Heart Association), cardiomyopathy and stroke or transient ischemic attack in the past two years.
Uncontrolled high blood pressure defined as systolic blood pressure ≥ 150 mm Hg and/or ≥ diastolic blood pressure ≥ 100 mm Hg within the last six months.
Subjects with active coronary heart disease manifested by angina, even if on medication.
25 % 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
Clinically significant mental disorder not adequately controlled by medical treatment.
History of chronic alcohol abuse (40 g/day, e.g. 3 glasses of beer or 2 glasses of wine for at least six months) and/or intravenous drug abuse (within the last six months). Subjects with a history of other substance and/or alcohol abuse are also excluded if - in the opinion of the investigator - the abuse could prevent the subject from complying with study requirements.
History of allergic disease or reactions likely to be exacerbated by IMVAMUNE® or any component of the vaccine, e.g. tris(hydroxymethyl)-amino methane, chicken embryo fibroblast proteins, aminoglycosides (gentamycin).
History of anaphylactic shock or any severe allergic reaction to a vaccine requiring immediate treatment.
Subjects undergoing treatment for tuberculosis infection or disease.
Having received any vaccinations or planned vaccinations with a live vaccine within 30 days prior to or after study vaccination.
Having received any vaccinations or planned vaccinations with a killed vaccine within 14 days prior to or after study vaccination.
Administration or planned administration of immuno-globulins and/or any blood products during a period starting from three months prior to administration of the vaccine and ending at study conclusion.
Use of any investigational or non-registered drug or vaccine other than the study vaccine within 30 days preceding the first dose of the study vaccine or planned administration of such a drug during the study period.
Temperature ≥ 100.4°F (38.0°C) at the time of enrollment.
Any condition which might interfere with study objectives or would limit the subject's ability to complete the study in the opinion of the investigator.
Study personnel.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Richard N Greenberg, MD
Organizational Affiliation
University of Kentucky
Official's Role
Principal Investigator
Facility Information:
Facility Name
Orlando Clinical Research Center
City
Orlando
State/Province
Florida
ZIP/Postal Code
32809
Country
United States
Facility Name
University of Iowa
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
University of Kentucky, School of Medicine, Department of Medicine
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536-0084
Country
United States
Facility Name
University of Rochester, Medical Center
City
Rochester
State/Province
New York
ZIP/Postal Code
16462
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
27327616
Citation
Greenberg RN, Hay CM, Stapleton JT, Marbury TC, Wagner E, Kreitmeir E, Roesch S, von Krempelhuber A, Young P, Nichols R, Meyer TP, Schmidt D, Weigl J, Virgin G, Arndtz-Wiedemann N, Chaplin P. A Randomized, Double-Blind, Placebo-Controlled Phase II Trial Investigating the Safety and Immunogenicity of Modified Vaccinia Ankara Smallpox Vaccine (MVA-BN(R)) in 56-80-Year-Old Subjects. PLoS One. 2016 Jun 21;11(6):e0157335. doi: 10.1371/journal.pone.0157335. eCollection 2016.
Results Reference
derived
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A Study to Evaluate Safety and Immunogenicity of One and Two Doses of IMVAMUNE® Smallpox Vaccine in 56-80 Year Old Vaccinia-experienced Subjects
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