Staphylococcal Infections
Conditions
Keywords
S. aureus;, Vaccine, FIM
Brief summary
This is a randomized, Multicenter, double-blind (subject, investigator, and Merck Research Laboratories (MRL) clinical personnel directly involved in the study), placebo-controlled, dose-ranging study in healthy adults 18 to 55 years of age. It is the first in man (FIM) study evaluating the tolerability and immunogenicity of the 0657nI S. aureus vaccine. For this Phase I study, approximately 120 healthy adults will be enrolled in the study and randomized to receive a single 0.5 mL vaccination of either 0657nI S. aureus vaccine (3 different dosage levels of 5 μg, 30 μg or 90 μg of the 0657nI vaccine) or saline placebo. Vaccine/placebo will be administered intramuscularly (IM) in the deltoid muscle. Because this study will be the first study evaluating the tolerability and immunogenicity of 0657nI S. aureus vaccine in humans, a dose-escalation phase will be conducted in a small number of subjects randomized in a 3:1 ratio (n=36, consisting of 9 subjects for each of 3 vaccine dosage levels and 9 placebo subjects) to evaluate the vaccine safety at increasing dose levels of the 0657nI protein in Panel A, before expanding the enrollment to the remaining 84 subjects in Panel B.
Detailed description
Depending on when the subject is enrolled into the study, the following will be completed: The subject will receive a single injection of SAV or placebo (an inactive substance) in the deltoid muscle of the upper arm. The subject will then be watched for 30 minutes after vaccination to monitor for allergic reactions. The subject will be asked to visit the study doctor either 6 or 9 times during the 3-month study period. Once enrolled, the subject will have blood drawn before receiving the vaccine (baseline) and up to 7 times after that at each of the required visits. The blood will be used for tests and/or for testing the subject's body's immune response to the SAV, to see if the subjects have developed immunity to S. aureus and if immunity continues up to 84 days. A Vaccination Report Card (VRC) will be provided to all participants. The participant will be asked to record oral temperatures and any reactions that occur at the SAV injection site every day for 5 days after vaccination. The participant will also be asked to record any physical adverse effects that they may experience, including headaches, nausea, muscle pain or aches, and fatigue every day for 14 days after vaccination. In additional all medications (including over the counter medications) taken during the 14 days post vaccination will be recorded and the VRC will be returned to the research staff after 14 days.
Interventions
BIOLOGICALV710
Single dose of V710 (at dosages of 5 μg, 30 μg, or 90 μg) intramuscularly
BIOLOGICALComparator: Placebo
Single dose of saline placebo intramuscularly
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Subject is 18 to 55 years of age * Subject is in good physical health based upon medical history, physical examination, and screening laboratory studies. NOTE: Lab studies will only be collected in Panel A, the dose-escalating portion of the study * Subject is able to understand study procedures and agrees to participate in the study by providing written informed consent * Subject is willing and able to participate in the entire study duration planned for 3 months (\ 84 days) * Female subjects are required to have a negative urine pregnancy test immediately prior to study vaccination. Female subjects of childbearing potential must have been using an acceptable method of birth control for 2 weeks prior to enrollment, and agree to use an acceptable method of birth control for 1 month after vaccination. (Acceptable methods of birth control include use of hormonal contraceptives, intrauterine device (IUD), diaphragm with spermicide, contraceptive sponge, tubal ligation, condoms, or abstinence)
Exclusion criteria
* Subject suffers from a chronic skin condition that predisposes the individual to the development of chronic skin or soft-tissue infections (e.g., psoriasis, chronic granulomatous disease). * Subject developed a serious infection (e.g., bacteremia, pneumonia, mediastinitis) attributed to S. aureus in the 12 months prior to screening * Subject has a history of anaphylaxis to aluminum-containing adjuvant or other vaccine components * Subject has a temperature of ≥100.4ºF (≥38.0ºC), oral equivalent, within 48 hours prior to receipt of 0657nI S. aureus vaccine/placebo * Subject has received a live virus vaccine within 30 days prior to receipt of 0657nI S. aureus vaccine/placebo or is scheduled to receive vaccination with a live virus vaccine within 30 days following study entry * Subject has received any other licensed vaccine (including non-live virus vaccines) within 14 days prior to receipt of 0657nI S. aureus vaccine/placebo or is scheduled to receive any other licensed vaccine (including non-live virus vaccines) within 30 days following study entry. (Note: Influenza vaccines may be administered during the study, but must be given at least 7 days prior to receipt of the study vaccine or at least 15 days after receipt of the study vaccine) * Subject was administered immunoglobulin or blood product within 90 days prior to receipt of 0657nI S. aureus vaccine/placebo or is scheduled to receive such products within 30 days following study entry * Subject has received treatment with systemic (intramuscular, oral, or intravenous) corticosteroids or another immunosuppressive medication (e.g., calcineurin inhibitors, mycophenolate, azathioprine) in the 14 days prior to receipt of 0657nI S. aureus vaccine/placebo or is anticipated to receive such medications for a chronic medical condition during the course of the study * Subject has a condition that requires active medical intervention or monitoring to avert serious danger to the subject's health or well-being, such as diabetes mellitus, autoimmune disease, or clinically significant chronic medical conditions that are considered progressive, including but not limited to: coronary artery disease, congestive heart failure, cardiomyopathy, progressive valvular heart disease, chronic obstructive pulmonary disease, pulmonary fibrosis, active peptic ulcer disease, chronic renal disease, chronic hepatic disease, multiple sclerosis, progressive neuropathies, or seizure disorder requiring therapy in the past 3 years * Subject has known or suspected impairment of immunologic function including, but not limited to, the following conditions: autoimmune disease, diabetes mellitus, end-stage renal disease, hepatic insufficiency/cirrhosis, splenectomy, or HIV/AIDS * Subject has a condition in which repeated venipuncture or injections pose more than minimal risk for the subject, such as hemophilia, other severe coagulation disorders, or significantly impaired venous access * Subject is currently pregnant or breastfeeding, or planning to conceive within the 3-month study duration period * Subject has clinically significant abnormalities based on the subject's medical history, physical examination, or screening laboratory studies (as described in Appendix 1 of the Multicenter protocol). NOTE: Lab studies will only be collected in Panel A, the dose escalating portion of the study * Subject has recent history (within the past 5 years) or current evidence of drug or alcohol abuse * Subject has a major psychiatric illness, including any history of schizophrenia or severe psychosis, bipolar disorder requiring therapy, or any subject with suicidal ideation within the previous 3 years * Subject is legally or mentally incapacitated * Subject has participated in another clinical study in the past 4 weeks, or plans to participate in a treatment-based study or study in which an invasive procedure is to be performed while enrolled in this study. NOTE: Participation in a safety surveillance study is acceptable * Subject has a history of any condition which, in the opinion of the investigator, may pose an additional risk for the subject or confound the results of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Vaccine-related Serious Adverse Experiences Following Vaccination | Through Day 84 postvaccination | Participants with a serious vaccine-related adverse experiences (AE) (an AE which is assessed by an investigator/qualified physician as being related to study vaccine and results in death, persistent or significant disability/incapacity, prolongs an existing inpatient hospitalization, is life-threatening, a congenital anomaly/birth defect, a cancer, or an overdose). |
| Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 14 Postvaccination | Baseline and Day 14 postvaccination | — |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 7 Postvaccination | Baseline and Day 7 postvaccination |
Participant flow
Recruitment details
Phase I; First Subject In: 06-Dec-2005; Last Subject Out: 31-Jul-2006. Enrollment occurred at 6 investigative sites in the United States.
Pre-assignment details
Subject was 18 to 55 years old; in good physical health based upon medical history, physical exam, and screening tests; able to understand study procedures and provided written consent; willing and able to complete entire study; and (if female) provided negative urine pregnancy test before vaccination and using an accepted method of birth control.
Participants by arm
| Arm | Count |
|---|---|
| V710 5 μg V710 5 μg single dose at baseline. | 31 |
| V710 30 μg V710 30 μg single dose at baseline. | 28 |
| V710 90 μg V710 90 μg single dose at baseline. | 34 |
| Placebo Saline placebo single dose at baseline. | 31 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 2 |
| Overall Study | Recruitment into Army Reserves | 0 | 0 | 1 | 0 |
| Overall Study | subject moved | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | V710 5 μg | V710 30 μg | V710 90 μg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Customized 17 years of age and under | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Age, Customized 18 to 29 years of age | 10 participants | 5 participants | 8 participants | 10 participants | 33 participants |
| Age, Customized 30 to 39 years of age | 7 participants | 8 participants | 12 participants | 5 participants | 32 participants |
| Age, Customized 40 to 49 years of age | 11 participants | 8 participants | 11 participants | 11 participants | 41 participants |
| Age, Customized 50 to 55 years of age | 3 participants | 7 participants | 3 participants | 5 participants | 18 participants |
| Age, Customized Over 55 years of age | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 3 participants | 0 participants | 1 participants | 3 participants | 7 participants |
| Race/Ethnicity, Customized Black | 9 participants | 8 participants | 4 participants | 4 participants | 25 participants |
| Race/Ethnicity, Customized Hispanic-American | 1 participants | 1 participants | 2 participants | 0 participants | 4 participants |
| Race/Ethnicity, Customized Multiracial | 0 participants | 0 participants | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Native American | 0 participants | 0 participants | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized White | 18 participants | 19 participants | 26 participants | 21 participants | 84 participants |
| Sex: Female, Male Female | 13 Participants | 21 Participants | 16 Participants | 18 Participants | 68 Participants |
| Sex: Female, Male Male | 18 Participants | 7 Participants | 18 Participants | 13 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 31 | 19 / 28 | 28 / 34 | 17 / 31 |
| serious Total, serious adverse events | 0 / 31 | 0 / 28 | 0 / 34 | 0 / 31 |
Outcome results
Primary
Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 14 Postvaccination
Time frame: Baseline and Day 14 postvaccination
Population: The population analyzed was the per-protocol population, excluding subjects identified as protocol violators. Subjects who were found to have deviated from the protocol procedures were evaluated to determine if they should be excluded from the per-protocol analyses. These evaluations were made prior to study unblinding on a case by case basis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| V710 5 μg | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 14 Postvaccination | Fold-rise in antibody titer ≥2 | 9 Participants |
| V710 5 μg | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 14 Postvaccination | Fold-rise in antibody titer <2 | 22 Participants |
| V710 30 μg | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 14 Postvaccination | Fold-rise in antibody titer <2 | 4 Participants |
| V710 30 μg | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 14 Postvaccination | Fold-rise in antibody titer ≥2 | 24 Participants |
| V710 90 μg | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 14 Postvaccination | Fold-rise in antibody titer ≥2 | 27 Participants |
| V710 90 μg | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 14 Postvaccination | Fold-rise in antibody titer <2 | 4 Participants |
| Placebo | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 14 Postvaccination | Fold-rise in antibody titer ≥2 | 1 Participants |
| Placebo | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 14 Postvaccination | Fold-rise in antibody titer <2 | 27 Participants |
Comparison: Testing was performed in a sequential manner. First, the response rate of the 90-μg group was compared to placebo and assessed for significance (using a 1-tailed α=0.025). If significant, the response rate of the 30-μg group was compared to placebo and assessed for significance. The testing continued sequentially until a non-significant result was observed or until all V710 groups had been compared with placebo.p-value: <0.00195% CI: [65.2, 93.6]Chi-squared
Comparison: Testing was performed in a sequential manner. First, the response rate of the 90-μg group was compared to placebo and assessed for significance (using a 1-tailed α=0.025). If significant, the response rate of the 30-μg group was compared to placebo and assessed for significance. The testing continued sequentially until a non-significant result was observed or until all V710 groups had been compared with placebo.p-value: <0.0195% CI: [61.6, 92]Chi-squared
Comparison: Testing was performed in a sequential manner. First, the response rate of the 90-μg group was compared to placebo and assessed for significance (using a 1-tailed α=0.025). If significant, the response rate of the 30-μg group was compared to placebo and assessed for significance. The testing continued sequentially until a non-significant result was observed or until all V710 groups had been compared with placebo.p-value: <0.00195% CI: [6.7, 43.8]Chi-squared
Primary
Number of Vaccine-related Serious Adverse Experiences Following Vaccination
Participants with a serious vaccine-related adverse experiences (AE) (an AE which is assessed by an investigator/qualified physician as being related to study vaccine and results in death, persistent or significant disability/incapacity, prolongs an existing inpatient hospitalization, is life-threatening, a congenital anomaly/birth defect, a cancer, or an overdose).
Time frame: Through Day 84 postvaccination
Population: The population analyzed included all subjects who were randomized, vaccinated, and had safety follow-up.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| V710 5 μg | Number of Vaccine-related Serious Adverse Experiences Following Vaccination | Did not experience a vaccine-related SAE | 31 Participants |
| V710 5 μg | Number of Vaccine-related Serious Adverse Experiences Following Vaccination | Experienced a vaccine-related SAE | 0 Participants |
| V710 30 μg | Number of Vaccine-related Serious Adverse Experiences Following Vaccination | Experienced a vaccine-related SAE | 0 Participants |
| V710 30 μg | Number of Vaccine-related Serious Adverse Experiences Following Vaccination | Did not experience a vaccine-related SAE | 28 Participants |
| V710 90 μg | Number of Vaccine-related Serious Adverse Experiences Following Vaccination | Experienced a vaccine-related SAE | 0 Participants |
| V710 90 μg | Number of Vaccine-related Serious Adverse Experiences Following Vaccination | Did not experience a vaccine-related SAE | 34 Participants |
| Placebo | Number of Vaccine-related Serious Adverse Experiences Following Vaccination | Experienced a vaccine-related SAE | 0 Participants |
| Placebo | Number of Vaccine-related Serious Adverse Experiences Following Vaccination | Did not experience a vaccine-related SAE | 31 Participants |
Secondary
Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 7 Postvaccination
Time frame: Baseline and Day 7 postvaccination
Population: The population analyzed was the per-protocol population, excluding subjects identified as protocol violators. Subjects who were found to have deviated from the protocol procedures were evaluated to determine if they should be excluded from the per-protocol analyses. These evaluations were made prior to study unblinding on a case by case basis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| V710 5 μg | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 7 Postvaccination | Fold-rise in antibody titer ≥2 | 1 Participants |
| V710 5 μg | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 7 Postvaccination | Fold-rise in antibody titer <2 | 30 Participants |
| V710 30 μg | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 7 Postvaccination | Fold-rise in antibody titer <2 | 24 Participants |
| V710 30 μg | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 7 Postvaccination | Fold-rise in antibody titer ≥2 | 4 Participants |
| V710 90 μg | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 7 Postvaccination | Fold-rise in antibody titer <2 | 23 Participants |
| V710 90 μg | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 7 Postvaccination | Fold-rise in antibody titer ≥2 | 10 Participants |
| Placebo | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 7 Postvaccination | Fold-rise in antibody titer ≥2 | 0 Participants |
| Placebo | Number of Participants With ≥2-fold Rise in Antibody Titer From Baseline at Day 7 Postvaccination | Fold-rise in antibody titer <2 | 30 Participants |
Comparison: Testing was performed in a sequential manner. First, the response rate of the 90-μg group was compared to placebo and assessed for significance (using a 1-tailed α=0.025). If significant, the response rate of the 30-μg group was compared to placebo and assessed for significance. The testing continued sequentially until a non-significant result was observed or until all V710 groups had been compared with placebo.p-value: <0.00195% CI: [17.2, 48.3]Chi-squared
Comparison: Testing was performed in a sequential manner. First, the response rate of the 90-μg group was compared to placebo and assessed for significance (using a 1-tailed α=0.025). If significant, the response rate of the 30-μg group was compared to placebo and assessed for significance. The testing continued sequentially until a non-significant result was observed or until all V710 groups had been compared with placebo.p-value: <0.00195% CI: [1.6, 32.1]Chi-squared
Comparison: Testing was performed in a sequential manner. First, the response rate of the 90-μg group was compared to placebo and assessed for significance (using a 1-tailed α=0.025). If significant, the response rate of the 30-μg group was compared to placebo and assessed for significance. The testing continued sequentially until a non-significant result was observed or until all V710 groups had been compared with placebo.p-value: <0.00195% CI: [-8.2, 16.9]Chi-squared