Tuberculosis
Conditions
Keywords
Mycobacterium tuberculosis infection, Healthy adolescents, Healthy participants, BCG vaccine
Brief summary
The purpose of this study is to demonstrate the efficacy of Bacille Calmette Guerin (BCG) revaccination against sustained Mycobacterium tuberculosis infection versus placebo in previously BCG vaccinated QuantiFERON®-TB Gold Plus Assay (QFT) negative, healthy adolescents.
Interventions
BIOLOGICALBCG vaccine SSI
Participants will receive a single 0.1 milliliter (mL) volume of BCG vaccine SSI, administered intradermally in deltoid region of the upper arm.
BIOLOGICALPlacebo
Participants will receive a single 0.1 mL volume of normal saline, administered intradermally in deltoid region of the upper arm.
Sponsors
Gates Medical Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
10 Years to 18 Years
Healthy volunteers
Yes
Inclusion criteria
* Participant between ≥ 10 years and ≤ 18 years on Study Day 1 * General good health, confirmed by medical history and physical examination * Vaccinated with Bacille Calmette Guerin (BCG) at least 5 years ago, documented through medical history or by presence of healed BCG scar * Tests QuantiFERON®-TB Gold Plus Assay (QFT) negative at screening. * For female participants: not pregnant and agrees to avoid pregnancy throughout the first 12 months of the study. Women physically capable of pregnancy must agree to use an acceptable method of avoiding pregnancy during this period. Acceptable methods of avoiding pregnancy include sexual abstinence (not engaging in sexual intercourse), a confirmed sterile partner, or at least 2 contraception methods from the following list: male or female condom, diaphragm, intrauterine devices (IUDs), hormonal contraceptive (oral, injection, transdermal patch, or implant). * Agrees to stay in contact with the study site for the duration of the study, provide updated contact information as necessary, and has no current plans to move from the study area for the duration of the study * Capable of giving signed informed consent/assent and completes the written informed consent/assent process.
Exclusion criteria
* Acute illness on Study Day 1. NOTE: This is a temporary exclusion for which the participant may be re-evaluated * Body temperature ≥37.5 degree Celsius on Study Day 1. NOTE: This is a temporary exclusion for which the participant may be re-evaluated * History or evidence of any clinically significant disease, including severe eczema and severe asthma, or any acute or chronic illness that might affect the safety, immunogenicity, or efficacy of study vaccine in the opinion of the investigator * Any current medical, psychiatric, occupational, or substance abuse problems that, in the opinion of the investigator, will make it unlikely that the participant will comply with the protocol * History of autoimmune disease * History or evidence of active tuberculosis (TB) disease * History or laboratory evidence of any past or present possible immunodeficiency state including, but not limited to, any laboratory indication of human immunodeficiency virus - 1 (HIV-1) infection * History of allergic disease that is likely to be exacerbated by any component of the study vaccine * History of treatment for active TB disease or history of latent Mycobacterium tuberculosis infection * Received a tuberculin skin test within 6 months prior to Study Day 1 * Received immunosuppressive treatment, e.g., chemotherapy, biologics or radiation therapy, or used immunosuppressive medication (daily steroid equivalent of ≥5 milligrams prednisone) within 42 days before Study Day 1. Inhaled and topical corticosteroids are permitted. * Received immunoglobulin or blood products within 42 days before Study Day 1 * Planned administration/administration of a licensed vaccine in the period starting 28 days before and ending 28 days after Study Day 1 * Received investigational TB vaccine at any time prior to Study Day 1 * Received any investigational drug therapy or investigational vaccine within 180 days before Study Day 1, or planned participation in any other clinical trial using investigational product during the study period * Laboratory values from the most recent blood collected prior to randomization outside the normal range that are suggestive of a disease state. Grade 1 abnormalities (as per Division of Acquired Immunodeficiency Syndrome toxicity table version 2.1) do not lead to exclusion if the investigator considers them not clinically significant * Urinalysis abnormality greater than Grade 1 on the Toxicity Scale (with the exception of hematuria in a menstruating female), or urinalysis abnormality judged clinically significant by the investigator * Shared residence with an individual who is receiving TB treatment or with someone who is known to have incompletely treated TB. e.g., Xpert Mycobacterium tuberculosis (MTB)/rifampicin (RIF) assay-positive, polymerase chain reaction-positive, culture-positive, smear-positive TB, or clinically diagnosed unconfirmed TB * Child in Care * Female participants currently pregnant or lactating/nursing; or positive serum pregnancy test during screening or on Day 1, prior to vaccination, or planning a pregnancy within the first 12 months after study intervention
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Sustained QuantiFERON®-TB Gold Plus Assay (QFT) Conversion From a Negative to Positive Test Based on Positive QFT Test Results | Up to 48 months | Sustained conversion was defined as sustained QFT conversion from a negative to positive test, with initial conversion at any time after a first negative QFT result post randomization (Day 71 or subsequent visit if Day 71 result was not available), and remaining QFT positive at 3- and 6-months post-conversion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Sustained QFT Conversion From a Negative to Positive Test Based on Positive QFT Test Results at 48-Months Follow-up or Discontinued Early | 48 Months Follow-up | Sustained conversion was defined as sustained QFT conversion from a negative to positive test, with initial conversion at any time after a first negative QFT result post randomization (Day 71 or subsequent visit if Day 71 result was not available), and remaining QFT positive at 3- and 6-months post-conversion. |
| Number of Participants With Serious and Non-serious Solicited Adverse Events (AEs) Through 7 Days Post Vaccination | Day 1 through Day 7 | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An AE does not necessarily have a causal relationship with the intervention. Solicited AEs were defined as events that participants were specifically asked about and which were noted by participants in the diary card. Solicited AEs included injection site symptoms of injections site pain, redness and swelling and general body symptoms such as headache, fatigue, gastrointestinal symptoms, and fever. |
| Number of Participants With Unsolicited AEs Through Day 28, as Well as Solicited AEs That Were Ongoing at Day 7 After Vaccination | Day 1 through Day 28 | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An AE does not necessarily have a causal relationship with the intervention. Unsolicited AEs were all AEs for which the participants were not specifically questioned in the participant diary card, as well as solicited AEs that were ongoing at Day 7 after vaccination. Number of Participants With Unsolicited AEs Through 28 Days after vaccination has been presented. |
| Number of Participants With Sustained QFT Conversion From a Negative to Positive Test Based on Positive QFT Test Results at 36-Months Follow-up or Discontinued Early | 36 Months Follow-up | Sustained conversion was defined as sustained QFT conversion from a negative to positive test, with initial conversion at any time after a first negative QFT result post randomization (Day 71 or subsequent visit if Day 71 result was not available), and remaining QFT positive at 3- and 6-months post-conversion. |
| Number of Participants With AEs of Special Interest | Up to 6 months | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. AE of special interest are AEs that the sponsor closely monitors. The AEs of special interest to be collected and reported include immune system disorders (anaphylactic reaction), general disorders (disseminated BCG disease), infections and infestations (osteomyelitis, suppurative lymphadenitis, injection site abscess), skin and subcutaneous tissue disorders (injection site lupus vulgaris, injection site keloid formation), and bone disorders (osteitis). |
| Number of Participants With Serious Adverse Drug Reactions (ADRs) | Up to 48 months | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. When an AE is judged to be serious and related to an investigational product, it is a Serious ADR. |
| Number of Participants With Serious Adverse Events (SAEs) | Up to 6 months | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment. Number of Participants reporting SAEs has been presented. |
Countries
South Africa
Participant flow
Recruitment details
This was a Phase IIb, randomized, placebo-controlled, observer-blind study to evaluate the efficacy, safety, and immunogenicity of Bacille Calmette Guerin (BCG) revaccination against sustained Mycobacterium tuberculosis infection versus placebo in previously BCG vaccinated QuantiFERON®-TB Gold Plus Assay (QFT) negative, healthy adolescents.
Pre-assignment details
A total of 1836 participants were enrolled from South African and were randomized 1:1 to experimental and placebo groups.
Participants by arm
| Arm | Count |
|---|---|
| Bacille Calmette Guerin (BCG) Group Participants were randomized to receive a single 0.1 mL volume of BCG vaccine SSI, administered intradermally in deltoid region of the upper arm. | 918 |
| Placebo Group Participants were randomized to receive a single 0.1 mL volume of normal saline, administered intradermally in deltoid region of the upper arm. | 917 |
| Total | 1,835 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 9 | 3 |
| Overall Study | Other | 20 | 18 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Sponsor termination of study | 750 | 755 |
| Overall Study | Withdrawal by Subject | 29 | 28 |
Baseline characteristics
| Characteristic | Bacille Calmette Guerin (BCG) Group | Placebo Group | Total |
|---|---|---|---|
| Age, Continuous | 13.4 Years STANDARD_DEVIATION 1.68 | 13.4 Years STANDARD_DEVIATION 1.67 | 13.4 Years STANDARD_DEVIATION 1.67 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 625 Participants | 627 Participants | 1252 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 292 Participants | 290 Participants | 582 Participants |
| Race/Ethnicity, Customized Asian Indian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 729 Participants | 735 Participants | 1464 Participants |
| Race/Ethnicity, Customized Mixed Race | 63 Participants | 61 Participants | 124 Participants |
| Race/Ethnicity, Customized Southern African Colored | 125 Participants | 120 Participants | 245 Participants |
| Race/Ethnicity, Customized White | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 474 Participants | 469 Participants | 943 Participants |
| Sex: Female, Male Male | 444 Participants | 448 Participants | 892 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 918 | 1 / 917 |
| other Total, other adverse events | 800 / 918 | 540 / 917 |
| serious Total, serious adverse events | 3 / 918 | 3 / 917 |
Outcome results
Primary
Number of Participants With Sustained QuantiFERON®-TB Gold Plus Assay (QFT) Conversion From a Negative to Positive Test Based on Positive QFT Test Results
Sustained conversion was defined as sustained QFT conversion from a negative to positive test, with initial conversion at any time after a first negative QFT result post randomization (Day 71 or subsequent visit if Day 71 result was not available), and remaining QFT positive at 3- and 6-months post-conversion.
Time frame: Up to 48 months
Population: Modified Intention to Treat Efficacy Population comprised of all participants randomly assigned to study intervention who received the study intervention, and are QFT negative at the Day 71 visit, or at the first study visit post Day 71 for which a QFT result is available if the Day 71 study visit was missed or the Day 71 QFT result was not available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bacille Calmette Guerin (BCG) Group | Number of Participants With Sustained QuantiFERON®-TB Gold Plus Assay (QFT) Conversion From a Negative to Positive Test Based on Positive QFT Test Results | 82 Participants |
| Placebo Group | Number of Participants With Sustained QuantiFERON®-TB Gold Plus Assay (QFT) Conversion From a Negative to Positive Test Based on Positive QFT Test Results | 78 Participants |
95% CI: [-0.431, 0.23]
p-value: 0.619395% CI: [0.77, 1.431]Log Rank
Secondary
Number of Participants With AEs of Special Interest
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. AE of special interest are AEs that the sponsor closely monitors. The AEs of special interest to be collected and reported include immune system disorders (anaphylactic reaction), general disorders (disseminated BCG disease), infections and infestations (osteomyelitis, suppurative lymphadenitis, injection site abscess), skin and subcutaneous tissue disorders (injection site lupus vulgaris, injection site keloid formation), and bone disorders (osteitis).
Time frame: Up to 6 months
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bacille Calmette Guerin (BCG) Group | Number of Participants With AEs of Special Interest | Injection site abscess | 4 Participants |
| Bacille Calmette Guerin (BCG) Group | Number of Participants With AEs of Special Interest | Suppurative lymphadenitis (Lymphadenitis bacterial) | 1 Participants |
| Bacille Calmette Guerin (BCG) Group | Number of Participants With AEs of Special Interest | Anaphylactic reaction | 0 Participants |
| Bacille Calmette Guerin (BCG) Group | Number of Participants With AEs of Special Interest | Disseminated BCG disease | 0 Participants |
| Bacille Calmette Guerin (BCG) Group | Number of Participants With AEs of Special Interest | Osteomyelitis | 0 Participants |
| Bacille Calmette Guerin (BCG) Group | Number of Participants With AEs of Special Interest | Injection site lupus vulgaris | 0 Participants |
| Bacille Calmette Guerin (BCG) Group | Number of Participants With AEs of Special Interest | Injection site keloid formation | 0 Participants |
| Bacille Calmette Guerin (BCG) Group | Number of Participants With AEs of Special Interest | Osteitis | 0 Participants |
| Placebo Group | Number of Participants With AEs of Special Interest | Osteitis | 0 Participants |
| Placebo Group | Number of Participants With AEs of Special Interest | Injection site abscess | 0 Participants |
| Placebo Group | Number of Participants With AEs of Special Interest | Osteomyelitis | 0 Participants |
| Placebo Group | Number of Participants With AEs of Special Interest | Suppurative lymphadenitis (Lymphadenitis bacterial) | 0 Participants |
| Placebo Group | Number of Participants With AEs of Special Interest | Injection site keloid formation | 0 Participants |
| Placebo Group | Number of Participants With AEs of Special Interest | Anaphylactic reaction | 0 Participants |
| Placebo Group | Number of Participants With AEs of Special Interest | Injection site lupus vulgaris | 0 Participants |
| Placebo Group | Number of Participants With AEs of Special Interest | Disseminated BCG disease | 0 Participants |
Secondary
Number of Participants With Serious Adverse Drug Reactions (ADRs)
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. When an AE is judged to be serious and related to an investigational product, it is a Serious ADR.
Time frame: Up to 48 months
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bacille Calmette Guerin (BCG) Group | Number of Participants With Serious Adverse Drug Reactions (ADRs) | 0 Participants |
| Placebo Group | Number of Participants With Serious Adverse Drug Reactions (ADRs) | 0 Participants |
Secondary
Number of Participants With Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment. Number of Participants reporting SAEs has been presented.
Time frame: Up to 6 months
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bacille Calmette Guerin (BCG) Group | Number of Participants With Serious Adverse Events (SAEs) | 3 Participants |
| Placebo Group | Number of Participants With Serious Adverse Events (SAEs) | 3 Participants |
Secondary
Number of Participants With Serious and Non-serious Solicited Adverse Events (AEs) Through 7 Days Post Vaccination
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An AE does not necessarily have a causal relationship with the intervention. Solicited AEs were defined as events that participants were specifically asked about and which were noted by participants in the diary card. Solicited AEs included injection site symptoms of injections site pain, redness and swelling and general body symptoms such as headache, fatigue, gastrointestinal symptoms, and fever.
Time frame: Day 1 through Day 7
Population: Safety Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bacille Calmette Guerin (BCG) Group | Number of Participants With Serious and Non-serious Solicited Adverse Events (AEs) Through 7 Days Post Vaccination | Any injection site symptom | 754 Participants |
| Bacille Calmette Guerin (BCG) Group | Number of Participants With Serious and Non-serious Solicited Adverse Events (AEs) Through 7 Days Post Vaccination | Any general body symptom | 371 Participants |
| Placebo Group | Number of Participants With Serious and Non-serious Solicited Adverse Events (AEs) Through 7 Days Post Vaccination | Any injection site symptom | 381 Participants |
| Placebo Group | Number of Participants With Serious and Non-serious Solicited Adverse Events (AEs) Through 7 Days Post Vaccination | Any general body symptom | 314 Participants |
Secondary
Number of Participants With Sustained QFT Conversion From a Negative to Positive Test Based on Positive QFT Test Results at 36-Months Follow-up or Discontinued Early
Sustained conversion was defined as sustained QFT conversion from a negative to positive test, with initial conversion at any time after a first negative QFT result post randomization (Day 71 or subsequent visit if Day 71 result was not available), and remaining QFT positive at 3- and 6-months post-conversion.
Time frame: 36 Months Follow-up
Population: mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bacille Calmette Guerin (BCG) Group | Number of Participants With Sustained QFT Conversion From a Negative to Positive Test Based on Positive QFT Test Results at 36-Months Follow-up or Discontinued Early | 74 Participants |
| Placebo Group | Number of Participants With Sustained QFT Conversion From a Negative to Positive Test Based on Positive QFT Test Results at 36-Months Follow-up or Discontinued Early | 73 Participants |
95% CI: [-0.395, 0.27]
p-value: 0.522495% CI: [0.73, 1.395]Log Rank
Secondary
Number of Participants With Sustained QFT Conversion From a Negative to Positive Test Based on Positive QFT Test Results at 48-Months Follow-up or Discontinued Early
Sustained conversion was defined as sustained QFT conversion from a negative to positive test, with initial conversion at any time after a first negative QFT result post randomization (Day 71 or subsequent visit if Day 71 result was not available), and remaining QFT positive at 3- and 6-months post-conversion.
Time frame: 48 Months Follow-up
Population: mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bacille Calmette Guerin (BCG) Group | Number of Participants With Sustained QFT Conversion From a Negative to Positive Test Based on Positive QFT Test Results at 48-Months Follow-up or Discontinued Early | 82 Participants |
| Placebo Group | Number of Participants With Sustained QFT Conversion From a Negative to Positive Test Based on Positive QFT Test Results at 48-Months Follow-up or Discontinued Early | 78 Participants |
95% CI: [-0.431, 0.23]
p-value: 0.619395% CI: [0.77, 1.431]Log Rank
Secondary
Number of Participants With Unsolicited AEs Through Day 28, as Well as Solicited AEs That Were Ongoing at Day 7 After Vaccination
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An AE does not necessarily have a causal relationship with the intervention. Unsolicited AEs were all AEs for which the participants were not specifically questioned in the participant diary card, as well as solicited AEs that were ongoing at Day 7 after vaccination. Number of Participants With Unsolicited AEs Through 28 Days after vaccination has been presented.
Time frame: Day 1 through Day 28
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bacille Calmette Guerin (BCG) Group | Number of Participants With Unsolicited AEs Through Day 28, as Well as Solicited AEs That Were Ongoing at Day 7 After Vaccination | 185 Participants |
| Placebo Group | Number of Participants With Unsolicited AEs Through Day 28, as Well as Solicited AEs That Were Ongoing at Day 7 After Vaccination | 117 Participants |