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Phase II Trial to Assess Safety and Immunogenicity of IMVAMUNE®

Primary Purpose

Smallpox

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
MVA Smallpox Vaccine
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Smallpox focused on measuring Smallpox, vaccine, IMVAMUNE, Stratis, parent protocol

Eligibility Criteria

18 Years - 40 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  1. 18 to 40 years of age, inclusive.
  2. Read, signed, and dated informed consent document.
  3. Available for follow-up for the planned duration of the study (six months after last immunization).
  4. Acceptable medical history by screening evaluation and limited physical assessment.
  5. If the subject is female and of childbearing potential, negative serum or urine pregnancy test at screening and within 24 hours prior to vaccination.
  6. If the subject is female and of childbearing potential*, she agrees to practice abstinence** or use acceptable contraception*** through 56 days after the last vaccination in order to avoid pregnancy:

    * a woman is considered of childbearing potential unless post-menopausal (>/= 1 year without menses) or surgically sterilized (tubal ligation, bilateral oophorectomy, or hysterectomy)

    **No sexual intercourse with men (vaginal penetration by a penis, coitus)

    ***Acceptable contraception methods are restricted to effective devices (IUDs, NuvaRing®) or licensed hormonal products with use of method for a minimum of 30 days prior to vaccination, condoms with spermicidal agents, monogamous relationship with a vasectomized partner who has been vasectomized for 6 months or more prior to study entry, or successful Essure placement with documented confirmation test at least 3 months after the procedure, and any other FDA-approved contraceptive method

  7. Negative test for HIV.
  8. Alanine Aminotransferase (ALT) <1.25 times the central lab upper limit of normal.
  9. Negative hepatitis B surface antigen and negative antibody to hepatitis C virus.
  10. Negative urine glucose and negative or trace urine protein by dipstick or urinalysis.
  11. Adequate renal function (defined as a serum creatinine not exceeding the central lab's upper limit of normal).
  12. Electrocardiogram (ECG) with no clinically significant abnormalities*

    * e.g., complete left or right bundle branch block, incomplete left bundle branch block or sustained ventricular arrhythmia, or two PVC's in a row, or ST elevation consistent with ischemia)

  13. Acceptable hematology parameters:

    • Hemoglobin (Hgb) equal or above the lower limit of central lab normal (sex-specific);
    • White Blood Cell (WBC) > 3,800 and < 10,900/mm^3;
    • Platelets >/=120,000/mm^3
  14. Body mass index >/=18.5-< 35.
  15. Be able to understand and comply with planned study procedures.

Exclusion Criteria:

  1. History of immunodeficiency.
  2. Typical vaccinia scar.
  3. Known or suspected history of smallpox vaccination including MVA alone or as a vector, as well as other investigational smallpox vaccines.
  4. Military service prior to 1991 or after January 2003.
  5. Known or suspected significant underlying illness including, but not limited to, clinically significant liver disease, diabetes mellitus, or moderate to severe kidney impairment.
  6. Malignancy (not including squamous cell skin cancer or basal cell skin cancer unless at the vaccination site) or history of skin cancer at the vaccination site.
  7. Active autoimmune disease. Persons with vitiligo or thyroid disease (e.g., taking thyroid hormone replacement) are not excluded.
  8. History of myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, or other heart condition under the care of a doctor*

    *Subjects with a not clinically relevant heart murmur, i.e., without any pathological ECG/arrhythmias or under treatment are not excluded.

  9. Systolic blood pressure >/= 150mmHg or diastolic blood pressure >/= 100mmHg.
  10. 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 (NCEP) risk assessment tool*

    *NOTE that this criterion applies only to subjects 20 years of age and older AND only if at least one of the following apply:

    • have smoked a cigarette in the past month, and/or
    • have hypertension (defined as systolic blood pressure >140 mm Hg) or are on antihypertensive medication, and/or
    • have a family history of coronary heart disease in male first-degree relative (father or brother) <55 years of age or a female first-degree relative (mother or sister) <65 years of age

    URL for NCEP risk assessment tool: http://cvdrisk.nhlbi.nih.gov/calculator.asp (if a subject has an HDL of greater than 100mg/dl please enter 100 in the tool)

  11. High-dose corticosteroid use for greater than 2 weeks duration within three months prior to vaccination or current use of immunosuppressive medication:

    • >5 mg prednisone or equivalent is considered high dose and immunosuppressive
    • Corticosteroid nasal sprays for allergic rhinitis are permissible
    • Persons who are using a topical steroid for mild uncomplicated dermatitis such as poison ivy or contact dermatitis may be enrolled the day after their therapy is completed
    • Inhaled steroids for asthma are not permissible
    • Oral/parenteral corticosteroids given for non-chronic conditions not expected to recur are permissible if the length of therapy was </= 14 days with completion at least 30 days prior to enrollment.
  12. Medical or psychiatric condition or occupational responsibilities that preclude subject compliance with the protocol.
  13. Any history of illegal injection drug use.
  14. Receipt or planned receipt of inactivated vaccine from 14 days prior to the first vaccination through 14 days post second vaccination.
  15. Receipt or planned receipt of any other live attenuated vaccine within 30 days prior to the first vaccination through 30 days post second vaccination.
  16. Use of any other experimental agent within 30 days prior to vaccination and for the duration of the subject's participation in the study.
  17. Receipt of blood products or immunoglobulin, including Rhogam, within six months prior to vaccination.
  18. Donation of a unit of blood within 56 days prior to vaccination or planned donation prior to 28-days following the last vaccination.
  19. Pregnant or breastfeeding women.
  20. Active exfoliative skin disorders/conditions, current varicella zoster virus infection, or any acute skin disorders of large magnitude, e.g., laceration requiring sutures, burn greater than 2×2 cm.
  21. Any condition that, in the opinion of the investigator, might interfere with assessing the study objectives.
  22. Known allergy to egg, aminoglycoside (including gentamicin) or chicken.
  23. Study personnel.
  24. Allergic reaction to any vaccine.

Sites / Locations

  • Emory Vaccine Center - The Hope Clinic
  • University of Iowa - Vaccine Research and Education Unit
  • University of Maryland Medical System - General Clinical Research Center (GCRC)
  • Saint Louis University - Center for Vaccine Development
  • Baylor College of Medicine - Molecular Virology and Microbiology
  • Group Health Research Institute - Seattle - Vaccines and Infectious Diseases

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Arm C

Arm B

Arm A

Arm D

Arm Description

88 subjects receive IMVAMUNE® 1x10^8 TCID50/0.5 mL subcutaneously (SC) via syringe and needle on Days 1 and 22.

88 subjects receive IMVAMUNE® 1x10^8 TCID50/0.5 mL subcutaneously (SC) via syringe and needle on Days 1 and 15.

88 subjects receive IMVAMUNE® 1x10^8 TCID50/0.5 mL subcutaneously (SC) via syringe and needle on Days 1 and 29.

88 subjects receive IMVAMUNE® 1x10^8 TCID50/0.5 mL subcutaneously (SC) via Stratis™ on Days 1 and 29.

Outcomes

Primary Outcome Measures

Geometric Mean Peak Plaque Reduction Neutralization Titer (PRNT) After Second Vaccination
Blood was collected from all participants at 8, 15, 22 and 29 days after receipt of the second vaccination for assessment of plaque reduction neutralization titers. The peak titer for each participant was defined as the highest titer among all available measurements post second vaccination. The geometric mean for each group was then assessed from individual participants' peak titers.
Percentage of Participants Reporting Moderate or Severe Solicited Local Injection Site Reactions After Receiving Vaccine Via the Stratis™ Compared to Syringe and Needle Administration
Participants maintained a memory aid to record daily the occurrence of local injection site reactions for 15 days after vaccination based on their interference with daily activities (pain and itchiness at injection site, underarm pain and swelling) or based on a quantitative measurement of the reaction (redness, swelling). In the subjective grading scale, severe reactions prevented daily activities, moderate reactions interfered with but did not prevent daily activities, and mild reactions were present but did not interfere with daily activities. For the quantitative scale, severe reactions greater than 30 millimeters (mm), moderate reactions were 15-30mm, and mild reactions were 1-15mm. Participants are counted by the maximum severity on any of the 15 days, and for this outcome measure, only those reporting moderate or severe events are counted. Formal comparisons by Fisher's Exact test were conducted for Arm D (Stratis, Day 1,29) compared to A

Secondary Outcome Measures

Geometric Mean Peak ELISA Titer After Second Vaccination
Blood was collected from all participants at 8, 15, 22 and 29 days after receipt of the second vaccination for assessment of antibody titers by ELISA. The peak titer for each participant was defined as the highest titer among all available measurements post second vaccination. The geometric mean for each group was then assessed from individual participants' peak titers.
Number of Subjects Experiencing Serious Adverse Events (SAEs) Associated With IMVAMUNE
Serious adverse events included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation thereof; was a congenital anomaly/birth defect; or may have jeopardized the participant, or required intervention to prevent one of the outcomes. Association with IMVAMUNE was determined by the investigator and defined as "Related", meaning a reasonable possibility that the study product caused the adverse event. Reasonable possibility was defined as there being evidence to suggest a causal relationship between the study product and the adverse event.

Full Information

First Posted
April 4, 2013
Last Updated
July 28, 2016
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT01827371
Brief Title
Phase II Trial to Assess Safety and Immunogenicity of IMVAMUNE®
Official Title
A Phase II, Randomized, Open-Label Study to Evaluate the Safety and Immunogenicity of IMVAMUNE® Using Three Immunization Schedules and Two Modes of Delivery
Study Type
Interventional

2. Study Status

Record Verification Date
May 2015
Overall Recruitment Status
Completed
Study Start Date
June 2013 (undefined)
Primary Completion Date
April 2015 (Actual)
Study Completion Date
April 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

Brief Summary
Imvamune (licensed name of MVA being developed as a smallpox vaccine) has been tested in over 2,000 individuals and is on path for licensure. This study will be a Phase II to evaluate three different immunization schedules and two different modes of delivery. The study will look at condensed schedules. Study will randomize subjects to one of four arms.
Detailed Description
This is a Phase II, randomized, open-label immunogenicity and safety study of different immunization schedules and delivery systems (syringe and needle vs. the Stratis™) in healthy, vaccinia-naïve adults 18 years to 40 years of age, inclusive. Approximately 352 subjects will be enrolled and randomized to one of four study arms. Study Arm A (N=88) will receive a two dose regimen of IMVAMUNE® (1x10^8 TCID50/0.5 mL per dose) via the SC route using a syringe and needle on Day 1 and 29. Study Arm B (N=88) will receive a two dose regimen of IMVAMUNE® (1x10^8 TCID50/0.5 mL per dose) via the SC route using a syringe and needle on Day 1 and 15. Study Arm C (N=88) will receive a two dose regimen of IMVAMUNE® (1x10^8 TCID50/0.5 mL) via the SC route using a syringe and needle on Day 1 and 22. Study Arm D (N=88) will receive a two dose regimen of IMVAMUNE® (1x10^8 TCID50/0.5 mL) via the SC route using the Stratis™ on Day 1 and 29. Immunogenicity assessments will be performed using ELISA and PRNT. Safety assessments will be done via solicited injection site and systemic reactions. Unsolicited AEs will be collected until 28 days post last injection and SAEs for the duration of the subjects' study participation. Safety laboratory assessments will be performed at baseline and 14 days after each vaccination. Primary outcome measures: For each subject, the peak PRNT will be defined as the highest titer among all available measurements post second vaccination; Occurrence of solicited local injection site reactions in subjects receiving vaccine via the Stratis™ compared to syringe and needle administration as collected on the memory aid and by in clinic assessment. Parent protocol to sub-study 13-0027.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Smallpox
Keywords
Smallpox, vaccine, IMVAMUNE, Stratis, parent protocol

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
435 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm C
Arm Type
Experimental
Arm Description
88 subjects receive IMVAMUNE® 1x10^8 TCID50/0.5 mL subcutaneously (SC) via syringe and needle on Days 1 and 22.
Arm Title
Arm B
Arm Type
Experimental
Arm Description
88 subjects receive IMVAMUNE® 1x10^8 TCID50/0.5 mL subcutaneously (SC) via syringe and needle on Days 1 and 15.
Arm Title
Arm A
Arm Type
Experimental
Arm Description
88 subjects receive IMVAMUNE® 1x10^8 TCID50/0.5 mL subcutaneously (SC) via syringe and needle on Days 1 and 29.
Arm Title
Arm D
Arm Type
Experimental
Arm Description
88 subjects receive IMVAMUNE® 1x10^8 TCID50/0.5 mL subcutaneously (SC) via Stratis™ on Days 1 and 29.
Intervention Type
Biological
Intervention Name(s)
MVA Smallpox Vaccine
Intervention Description
Subjects receive two dose regimen of IMVAMUNE® (1x10^8 TCID50/0.5 mL per dose) via the SC route using either a syringe and needle or the Stratis™ system. Arm A receives doses via syringe and needle on days 1 and 29; Arm B receives doses via syringe and needle on days 1 and 15, Arm C receives doses via syringe and needle on days 1 and 22, Arm D receives doses via Stratis on days 1 and 29.
Primary Outcome Measure Information:
Title
Geometric Mean Peak Plaque Reduction Neutralization Titer (PRNT) After Second Vaccination
Description
Blood was collected from all participants at 8, 15, 22 and 29 days after receipt of the second vaccination for assessment of plaque reduction neutralization titers. The peak titer for each participant was defined as the highest titer among all available measurements post second vaccination. The geometric mean for each group was then assessed from individual participants' peak titers.
Time Frame
Day 7 through Day 31 after 2nd vaccination
Title
Percentage of Participants Reporting Moderate or Severe Solicited Local Injection Site Reactions After Receiving Vaccine Via the Stratis™ Compared to Syringe and Needle Administration
Description
Participants maintained a memory aid to record daily the occurrence of local injection site reactions for 15 days after vaccination based on their interference with daily activities (pain and itchiness at injection site, underarm pain and swelling) or based on a quantitative measurement of the reaction (redness, swelling). In the subjective grading scale, severe reactions prevented daily activities, moderate reactions interfered with but did not prevent daily activities, and mild reactions were present but did not interfere with daily activities. For the quantitative scale, severe reactions greater than 30 millimeters (mm), moderate reactions were 15-30mm, and mild reactions were 1-15mm. Participants are counted by the maximum severity on any of the 15 days, and for this outcome measure, only those reporting moderate or severe events are counted. Formal comparisons by Fisher's Exact test were conducted for Arm D (Stratis, Day 1,29) compared to A
Time Frame
15 days after each vaccination
Secondary Outcome Measure Information:
Title
Geometric Mean Peak ELISA Titer After Second Vaccination
Description
Blood was collected from all participants at 8, 15, 22 and 29 days after receipt of the second vaccination for assessment of antibody titers by ELISA. The peak titer for each participant was defined as the highest titer among all available measurements post second vaccination. The geometric mean for each group was then assessed from individual participants' peak titers.
Time Frame
Day 7 through 31 after the 2nd vaccination
Title
Number of Subjects Experiencing Serious Adverse Events (SAEs) Associated With IMVAMUNE
Description
Serious adverse events included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation thereof; was a congenital anomaly/birth defect; or may have jeopardized the participant, or required intervention to prevent one of the outcomes. Association with IMVAMUNE was determined by the investigator and defined as "Related", meaning a reasonable possibility that the study product caused the adverse event. Reasonable possibility was defined as there being evidence to suggest a causal relationship between the study product and the adverse event.
Time Frame
Day 1 after the first vaccination through 180 days after the 2nd vaccination.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: 18 to 40 years of age, inclusive. Read, signed, and dated informed consent document. Available for follow-up for the planned duration of the study (six months after last immunization). Acceptable medical history by screening evaluation and limited physical assessment. If the subject is female and of childbearing potential, negative serum or urine pregnancy test at screening and within 24 hours prior to vaccination. If the subject is female and of childbearing potential*, she agrees to practice abstinence** or use acceptable contraception*** through 56 days after the last vaccination in order to avoid pregnancy: * a woman is considered of childbearing potential unless post-menopausal (>/= 1 year without menses) or surgically sterilized (tubal ligation, bilateral oophorectomy, or hysterectomy) **No sexual intercourse with men (vaginal penetration by a penis, coitus) ***Acceptable contraception methods are restricted to effective devices (IUDs, NuvaRing®) or licensed hormonal products with use of method for a minimum of 30 days prior to vaccination, condoms with spermicidal agents, monogamous relationship with a vasectomized partner who has been vasectomized for 6 months or more prior to study entry, or successful Essure placement with documented confirmation test at least 3 months after the procedure, and any other FDA-approved contraceptive method Negative test for HIV. Alanine Aminotransferase (ALT) <1.25 times the central lab upper limit of normal. Negative hepatitis B surface antigen and negative antibody to hepatitis C virus. Negative urine glucose and negative or trace urine protein by dipstick or urinalysis. Adequate renal function (defined as a serum creatinine not exceeding the central lab's upper limit of normal). Electrocardiogram (ECG) with no clinically significant abnormalities* * e.g., complete left or right bundle branch block, incomplete left bundle branch block or sustained ventricular arrhythmia, or two PVC's in a row, or ST elevation consistent with ischemia) Acceptable hematology parameters: Hemoglobin (Hgb) equal or above the lower limit of central lab normal (sex-specific); White Blood Cell (WBC) > 3,800 and < 10,900/mm^3; Platelets >/=120,000/mm^3 Body mass index >/=18.5-< 35. Be able to understand and comply with planned study procedures. Exclusion Criteria: History of immunodeficiency. Typical vaccinia scar. Known or suspected history of smallpox vaccination including MVA alone or as a vector, as well as other investigational smallpox vaccines. Military service prior to 1991 or after January 2003. Known or suspected significant underlying illness including, but not limited to, clinically significant liver disease, diabetes mellitus, or moderate to severe kidney impairment. Malignancy (not including squamous cell skin cancer or basal cell skin cancer unless at the vaccination site) or history of skin cancer at the vaccination site. Active autoimmune disease. Persons with vitiligo or thyroid disease (e.g., taking thyroid hormone replacement) are not excluded. History of myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, or other heart condition under the care of a doctor* *Subjects with a not clinically relevant heart murmur, i.e., without any pathological ECG/arrhythmias or under treatment are not excluded. Systolic blood pressure >/= 150mmHg or diastolic blood pressure >/= 100mmHg. 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 (NCEP) risk assessment tool* *NOTE that this criterion applies only to subjects 20 years of age and older AND only if at least one of the following apply: have smoked a cigarette in the past month, and/or have hypertension (defined as systolic blood pressure >140 mm Hg) or are on antihypertensive medication, and/or have a family history of coronary heart disease in male first-degree relative (father or brother) <55 years of age or a female first-degree relative (mother or sister) <65 years of age URL for NCEP risk assessment tool: http://cvdrisk.nhlbi.nih.gov/calculator.asp (if a subject has an HDL of greater than 100mg/dl please enter 100 in the tool) High-dose corticosteroid use for greater than 2 weeks duration within three months prior to vaccination or current use of immunosuppressive medication: >5 mg prednisone or equivalent is considered high dose and immunosuppressive Corticosteroid nasal sprays for allergic rhinitis are permissible Persons who are using a topical steroid for mild uncomplicated dermatitis such as poison ivy or contact dermatitis may be enrolled the day after their therapy is completed Inhaled steroids for asthma are not permissible Oral/parenteral corticosteroids given for non-chronic conditions not expected to recur are permissible if the length of therapy was </= 14 days with completion at least 30 days prior to enrollment. Medical or psychiatric condition or occupational responsibilities that preclude subject compliance with the protocol. Any history of illegal injection drug use. Receipt or planned receipt of inactivated vaccine from 14 days prior to the first vaccination through 14 days post second vaccination. Receipt or planned receipt of any other live attenuated vaccine within 30 days prior to the first vaccination through 30 days post second vaccination. Use of any other experimental agent within 30 days prior to vaccination and for the duration of the subject's participation in the study. Receipt of blood products or immunoglobulin, including Rhogam, within six months prior to vaccination. Donation of a unit of blood within 56 days prior to vaccination or planned donation prior to 28-days following the last vaccination. Pregnant or breastfeeding women. Active exfoliative skin disorders/conditions, current varicella zoster virus infection, or any acute skin disorders of large magnitude, e.g., laceration requiring sutures, burn greater than 2×2 cm. Any condition that, in the opinion of the investigator, might interfere with assessing the study objectives. Known allergy to egg, aminoglycoside (including gentamicin) or chicken. Study personnel. Allergic reaction to any vaccine.
Facility Information:
Facility Name
Emory Vaccine Center - The Hope Clinic
City
Decatur
State/Province
Georgia
ZIP/Postal Code
30030-1705
Country
United States
Facility Name
University of Iowa - Vaccine Research and Education Unit
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242-2600
Country
United States
Facility Name
University of Maryland Medical System - General Clinical Research Center (GCRC)
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201-1544
Country
United States
Facility Name
Saint Louis University - Center for Vaccine Development
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63104-1015
Country
United States
Facility Name
Baylor College of Medicine - Molecular Virology and Microbiology
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-3411
Country
United States
Facility Name
Group Health Research Institute - Seattle - Vaccines and Infectious Diseases
City
Seattle
State/Province
Washington
ZIP/Postal Code
98101-1466
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
28256358
Citation
Jackson LA, Frey SE, El Sahly HM, Mulligan MJ, Winokur PL, Kotloff KL, Campbell JD, Atmar RL, Graham I, Anderson EJ, Anderson EL, Patel SM, Fields C, Keitel W, Rouphael N, Hill H, Goll JB. Safety and immunogenicity of a modified vaccinia Ankara vaccine using three immunization schedules and two modes of delivery: A randomized clinical non-inferiority trial. Vaccine. 2017 Mar 23;35(13):1675-1682. doi: 10.1016/j.vaccine.2017.02.032. Epub 2017 Feb 27.
Results Reference
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Phase II Trial to Assess Safety and Immunogenicity of IMVAMUNE®

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