Tuberculosis
Conditions
Keywords
M. tuberculosis infection, isoniazid, HIV-exposed infants
Brief summary
Randomized controlled trial (RCT) of isoniazid (INH) vs. no INH to prevent Mycobacterium tuberculosis infection in HIV-exposed uninfected (HEU) infants.
Detailed description
The purpose of this trial is to determine whether isoniazid (INH) reduces the risk of Mycobacterium tuberculosis (MTB) infection in HIV-exposed but uninfected (HEU) children, as well as to determine epidemiologic and immunologic correlates of MTB infection in HEU.
Interventions
DRUGIsoniazid
HIV-exposed uninfected infants will be randomized to receive either INH or no INH daily for 12 months for the prevention of Mycobacterium tuberculosis (MTB) infection.
Sponsors
Thrasher Research Fund
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Weeks to 10 Weeks
Healthy volunteers
Yes
Inclusion criteria
* HIV exposed infants * Aged 6 weeks within (+ 4 weeks) * Born to HIV-infected mothers * Not premature and over 2.5 kg
Exclusion criteria
* Infants with known exposure to active TB in household * Premature and \< 2.5 kg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mycobacterium Tuberculosis (MTB) Infection | at 12 months post randomization | Among HEU infants enrolled at approximately 6 weeks of age, compare the risk of acquiring MTB infection during 1 year of follow-up in infants randomized to receive INH vs. no INH using an interferon-gamma release (IGRA) QuantiFERON-TB Gold Plus (QFT-Plus) assay or tuberculin skin test as part of a composite endpoint to determine MTB infection status |
| Mycobacterium Tuberculosis (MTB) Infection Cumulative Incidence | at 12 months post randomization | Among HEU infants enrolled at approximately 6 weeks of age, compare the risk of acquiring MTB infection during 1 year of follow-up in infants randomized to receive INH vs. no INH using an interferon-gamma release (IGRA) QuantiFERON-TB Gold Plus (QFT-Plus) assay or tuberculin skin test as part of a composite endpoint to determine MTB infection status |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Severe Adverse Events (SAE) | Over 12 months after randomization | Number of infants with grade 3 or higher treatment-related adverse events as assessed by DAIDS Table for the Grading Severity of Pediatric Adverse Experiences |
| Combined Outcome of MTB Infection, TB Disease, and Death | Over 12 months after randomization | Number of infants with a combined endpoint of MTB infection, TB disease, and death * MTB infection as measured by IGRA or tuberculin skin test at 12 months post-enrollment * TB disease including microbiologically confirmed (culture or Xpert positive), or probable TB (clinical diagnosis). * Death of infant |
| Combined Outcome of MTB Infection Including IGRA, TST, and Additional Interferon-gamma-independent Immune Markers in QFT-Plus Supernatants | Over 12 months after randomization | Number of infants with MTB infection as measured by * IGRA, or * Tuberculin skin test (\>10 mm) at 12 months post-enrollment, or * Interferon-gamma-independent immune markers in QFT-Plus supernatants Combined outcome will be defined as positive if IGRA OR TST OR interferon-gamma-independent marker is positive and combined outcome will be defined as negative if none of these is positive (if children do not have all three markers the definition will hold for available markers). |
Countries
Kenya
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Isoniazid Isoniazid (INH) \
10 mg/kg (7-15 mg/kg), will be administered once daily to infants in INH arm for 12 months.
Isoniazid: HIV-exposed uninfected infants will be randomized to receive either INH or no INH daily for 12 months for the prevention of Mycobacterium tuberculosis (MTB) infection. | 150 |
| No Isoniazid No INH will be administered to this arm. | 150 |
| Total | 300 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | HIV | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 5 |
| Overall Study | No TB infection endpoint | 14 | 9 |
| Overall Study | Withdrawal by Subject | 4 | 1 |
Baseline characteristics
| Characteristic | No Isoniazid | Total | Isoniazid |
|---|---|---|---|
| Age, Categorical <=18 years | 150 Participants | 300 Participants | 150 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 6.3 weeks | 6.3 weeks | 6.3 weeks |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Kenya | 150 participants | 300 participants | 150 participants |
| Sex: Female, Male Female | 71 Participants | 142 Participants | 71 Participants |
| Sex: Female, Male Male | 79 Participants | 158 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 150 | 1 / 150 |
| other Total, other adverse events | 0 / 150 | 0 / 150 |
| serious Total, serious adverse events | 21 / 150 | 16 / 150 |
Outcome results
Primary
Mycobacterium Tuberculosis (MTB) Infection
Among HEU infants enrolled at approximately 6 weeks of age, compare the risk of acquiring MTB infection during 1 year of follow-up in infants randomized to receive INH vs. no INH using an interferon-gamma release (IGRA) QuantiFERON-TB Gold Plus (QFT-Plus) assay or tuberculin skin test as part of a composite endpoint to determine MTB infection status
Time frame: at 12 months post randomization
Population: Final analysis 132 in Isoniazid (14 without endpoint and 4 discontinued) and 133 in No Isoniazid arm (9 without primary endpoint, 8 discontinued)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Isoniazid | Mycobacterium Tuberculosis (MTB) Infection | 10 participants |
| No Isoniazid | Mycobacterium Tuberculosis (MTB) Infection | 18 participants |
Primary
Mycobacterium Tuberculosis (MTB) Infection Cumulative Incidence
Among HEU infants enrolled at approximately 6 weeks of age, compare the risk of acquiring MTB infection during 1 year of follow-up in infants randomized to receive INH vs. no INH using an interferon-gamma release (IGRA) QuantiFERON-TB Gold Plus (QFT-Plus) assay or tuberculin skin test as part of a composite endpoint to determine MTB infection status
Time frame: at 12 months post randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Isoniazid | Mycobacterium Tuberculosis (MTB) Infection Cumulative Incidence | 7.0 TB infections/100 person years |
| No Isoniazid | Mycobacterium Tuberculosis (MTB) Infection Cumulative Incidence | 13.4 TB infections/100 person years |
Secondary
Combined Outcome of MTB Infection Including IGRA, TST, and Additional Interferon-gamma-independent Immune Markers in QFT-Plus Supernatants
Number of infants with MTB infection as measured by * IGRA, or * Tuberculin skin test (\>10 mm) at 12 months post-enrollment, or * Interferon-gamma-independent immune markers in QFT-Plus supernatants Combined outcome will be defined as positive if IGRA OR TST OR interferon-gamma-independent marker is positive and combined outcome will be defined as negative if none of these is positive (if children do not have all three markers the definition will hold for available markers).
Time frame: Over 12 months after randomization
Secondary
Combined Outcome of MTB Infection, TB Disease, and Death
Number of infants with a combined endpoint of MTB infection, TB disease, and death * MTB infection as measured by IGRA or tuberculin skin test at 12 months post-enrollment * TB disease including microbiologically confirmed (culture or Xpert positive), or probable TB (clinical diagnosis). * Death of infant
Time frame: Over 12 months after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Isoniazid | Combined Outcome of MTB Infection, TB Disease, and Death | 11 Participants |
| No Isoniazid | Combined Outcome of MTB Infection, TB Disease, and Death | 19 Participants |
Secondary
Severe Adverse Events (SAE)
Number of infants with grade 3 or higher treatment-related adverse events as assessed by DAIDS Table for the Grading Severity of Pediatric Adverse Experiences
Time frame: Over 12 months after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Isoniazid | Severe Adverse Events (SAE) | 21 Participants |
| No Isoniazid | Severe Adverse Events (SAE) | 16 Participants |