iTIPS: Infant TB Infection Prevention Study

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT02613169
• Collaborator: Thrasher Research Fund (Other)
• Enrollment: 300
• Location: 1
• Arms: 2
• Duration (Months): 52
• Patients Per Site Per Month: 5.8

Study Details

Study Description

Brief Summary

Randomized controlled trial (RCT) of isoniazid (INH) vs. no INH to prevent Mycobacterium tuberculosis infection in HIV-exposed uninfected (HEU) infants.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: Isoniazid	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 300 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Preventing Mycobacterium Tuberculosis Infection in HIV-Exposed Infants
• Study Start Date: Aug 1, 2016
• Actual Primary Completion Date: Oct 1, 2019
• Actual Study Completion Date: Dec 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Isoniazid Isoniazid (INH) ~10 mg/kg (7-15 mg/kg), will be administered once daily to infants in INH arm for 12 months.	Drug: 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.; Other Names: INH
No Intervention: No Isoniazid No INH will be administered to this arm.

Outcome Measures

Primary Outcome Measures

1. 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

2. 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 Outcome Measures

1. 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

2. 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

3. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Weeks to 10 Weeks
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kisumu County Hospital	Kisumu		Kenya

Sponsors and Collaborators

• University of Washington
• Thrasher Research Fund

Investigators

• Principal Investigator: Grace John-Stewart, MD, PhD, University of Washington, Dept of Global Health

Study Documents (Full-Text)

• Study Protocol - Apr 1, 2020
• Statistical Analysis Plan - Oct 22, 2019
• Informed Consent Form - Aug 11, 2017

More Information

Publications

• Madhi SA, Nachman S, Violari A, Kim S, Cotton MF, Bobat R, Jean-Philippe P, McSherry G, Mitchell C; P1041 Study Team. Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children. N Engl J Med. 2011 Jul 7;365(1):21-31. doi: 10.1056/NEJMoa1011214.
• Zar HJ, Cotton MF, Strauss S, Karpakis J, Hussey G, Schaaf HS, Rabie H, Lombard CJ. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ. 2007 Jan 20;334(7585):136. Epub 2006 Nov 3.

• Responsible Party: Grace John-Stewart, Professor, Global Health, Medicine, Epidemiology, Pediatrics, University of Washington
• ClinicalTrials.gov Identifier: NCT02613169
• Other Study ID Numbers: STUDY00000341
• First Posted: Nov 24, 2015
• Last Update Posted: Jun 10, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Grace John-Stewart, Professor, Global Health, Medicine, Epidemiology, Pediatrics, University of Washington: M. tuberculosis infection; isoniazid; HIV-exposed infants
• Additional relevant MeSH terms: Infections; Tuberculosis; Isoniazid

Study Results

Participant Flow

Arm/Group Title	Isoniazid	No Isoniazid
Arm/Group Description	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.	No INH will be administered to this arm.
Period Title: Overall Study
STARTED	150	150
COMPLETED	132	133
NOT COMPLETED	18	17

Baseline Characteristics

Arm/Group Title	Isoniazid	No Isoniazid	Total
Arm/Group Description	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.	No INH will be administered to this arm.	Total of all reporting groups
Overall Participants	150	150	300
Age (Count of Participants)
<=18 years	150 100%	150 100%	300 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (weeks) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [weeks]	6.3	6.3	6.3
Sex: Female, Male (Count of Participants)
Female	71 47.3%	71 47.3%	142 47.3%
Male	79 52.7%	79 52.7%	158 52.7%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Kenya	150 100%	150 100%	300 100%

Outcome Measures

1. Primary Outcome

Title	Mycobacterium Tuberculosis (MTB) Infection
Description	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

Outcome Measure Data

Analysis Population Description

Final analysis 132 in Isoniazid (14 without endpoint and 4 discontinued) and 133 in No Isoniazid arm (9 without primary endpoint, 8 discontinued)

Arm/Group Title	Isoniazid	No Isoniazid
Arm/Group Description	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.	No INH will be administered to this arm.
Measure Participants	132	133
Number [participants]	10 6.7%	18 12%

2. Secondary Outcome

Title	Severe Adverse Events (SAE)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isoniazid	No Isoniazid
Arm/Group Description	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.	No INH will be administered to this arm.
Measure Participants	150	150
Count of Participants [Participants]	21 14%	16 10.7%

3. Secondary Outcome

Title	Combined Outcome of MTB Infection, TB Disease, and Death
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isoniazid	No Isoniazid
Arm/Group Description	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.	No INH will be administered to this arm.
Measure Participants	146	142
Count of Participants [Participants]	11 7.3%	19 12.7%

4. Secondary Outcome

Title	Combined Outcome of MTB Infection Including IGRA, TST, and Additional Interferon-gamma-independent Immune Markers in QFT-Plus Supernatants
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Primary Outcome

Title	Mycobacterium Tuberculosis (MTB) Infection Cumulative Incidence
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isoniazid	No Isoniazid
Arm/Group Description	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.	No INH will be administered to this arm.
Measure Participants	132	133
Number [TB infections/100 person years]	7.0	13.4

Adverse Events

Time Frame	Adverse event data were collected throughout the study, for two years, two months.
Adverse Event Reporting Description	Adverse events include Grade ≥3 severe adverse events by DAIDS scale
Arm/Group Title	Isoniazid		No Isoniazid
Arm/Group Description	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.		No INH will be administered to this arm.
All Cause Mortality
	Isoniazid		No Isoniazid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/150 (0%)		1/150 (0.7%)
Serious Adverse Events
	Isoniazid		No Isoniazid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/150 (14%)		16/150 (10.7%)
Gastrointestinal disorders
Gastroenteritis	8/150 (5.3%)	8	3/150 (2%)	3
Infections and infestations
HIV infection	0/150 (0%)	0	2/150 (1.3%)	2
Malaria	12/150 (8%)	12	6/150 (4%)	6
Injury, poisoning and procedural complications
Burns	1/150 (0.7%)	1	0/150 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia/URTI	5/150 (3.3%)	5	5/150 (3.3%)	5
Surgical and medical procedures
Corrective surgery for spina bifida	0/150 (0%)	0	1/150 (0.7%)	1
Corrective surgery for cleft palate	1/150 (0.7%)	1	0/150 (0%)	0
Corrective surgery for encephalocele	1/150 (0.7%)	1	0/150 (0%)	0
Other (Not Including Serious) Adverse Events
	Isoniazid		No Isoniazid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/150 (0%)		0/150 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.