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Daily Isoniazid to Prevent Tuberculosis in Infants Born to Mothers With HIV

Primary Purpose

HIV Infection, Tuberculosis, Pneumocystis Jiroveci Pneumonia

Status

Terminated

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Isoniazid (INH)

Trimethoprim/Sulfamethoxazole (TMP/SMX)

Isoniazid Placebo (PL)

About this trial

This is an interventional prevention trial for HIV Infection focused on measuring Treatment Naive, INH Prophylaxis, HIV Seronegativity

Eligibility Criteria

91 Days - 120 Days (Child)All SexesAccepts Healthy Volunteers

Inclusion Criteria: Mother is HIV-infected. Hard copy documentation of the mother's HIV infection is unnecessary if a positive DNA PCR from her infant is available. Received Bacille Calmette-Guerin (BCG) vaccine up to and including the 30th day of life and at least 90 days prior to study entry Able to complete all study requirements Physician assessment of age-appropriate neurodevelopment in which the chronological age is corrected for gestational age for prematurely born infants Parent or legal guardian able and willing to provide signed informed consent Plan to live in the study area for at least 4 years For inclusion in HIV-infected stratum, infant must have a positive HIV-1 DNA PCR; for inclusion in HIV-uninfected stratum, infant must have a negative HIV-1 DNA PCR performed at >= 4 weeks of age Exclusion Criteria: Previous diagnosis of TB infection, TB disease or current treatment for TB infection or TB disease Previous receipt of INH Contact with a known acid fast bacilli (AFB) sputum smear or culture-positive case of TB before study entry Current acute or recurrent (3 or more prior episodes) lower respiratory tract disease Chronic persistent diarrhea Failure to thrive Contraindications for use of INH or TMP/SMX Require certain medications Known or suspected immune system diseases other than HIV Current or previous diagnosis of or treatment for cancer Current immunosuppressive therapy greater than 1 mg/kg/day of prednisone or equivalent Anticipated long-term oral or intravenous corticosteroid therapy (greater than 3 weeks). Those receiving nonsteroidal anti-inflammatory agents and inhaled corticosteroids are not excluded. Grade 3 or greater AST/SGOT, ALT/SGPT, ANC, hemoglobin, platelet count, rash, neuropathy, or myopathy at screening Any Grade 4 clinical or laboratory toxicity within 14 days prior to study entry Other acute or chronic conditions that, in the opinion of the investigator, may interfere with the study

Sites / Locations

Princess Marina Hospital
University of Cape Town, Red Cross Children's Hospital
University of Stellenbosch, Tygerberg Hospital
Nelson R. Mandela School of Medicine, University of KwaZulu Natal, Durban
Perinatal HIV Research Unit at Chris Hani Baragwanath Hospital
Chris Hani Baragwanath Hospital, Harriet Shezi Clinic

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

HIVneg/INH

HIVneg/PL

HIVpos/INH

HIVpos/PL

Arm Description

Perinatally exposed, HIV-uninfected (HIVneg) children receiving Isoniazid (INH)10-20 mg/kg orally once a day for 96 weeks + Trimethoprim/Sulfamethoxazole (TMP/SMX) 5 mg/kg of TMP component orally once a day until HIV status is confirmed and child is no longer at risk of acquiring HIV through breastfeeding

Perinatally exposed, HIV-uninfected (HIVneg) children receiving Isoniazid placebo (PL) orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until HIV status is confirmed and child is no longer at risk of acquiring HIV through breastfeeding

HIV-infected (HIVpos) children receiving Isoniazid (INH) 10-20 mg/kg orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until one year of age. TMP/SMX may have been continued after one year of age according to WHO guidelines.

HIV-infected (HIVpos) children receiving Isoniazid placebo (PL) orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until one year of age. TMP/SMX may have been continued after one year of age according to WHO guidelines.

Outcomes

Primary Outcome Measures

Time to Development of Tuberculosis (TB) Disease or Death Among HIV-infected Children

Criteria for diagnosis with TB disease: Definite-isolation of Mycobacterium TB (M.tb) or +ve stain on cerebrospinal fluid (CSF); Probable- +ve acid fast bacilli (AFB) stain on fluids/tissues other than CSF and sufficient clinical criteria/radiographic evidence suggestive of TB; Possible-abnormal chest radiograph suggestive of pulmonary TB (PTB) and either a +ve tuberculin skin test (TST) or minimum score on algorithm for clinical TB. Records reviewed by Endpoint Review Group. Results report percent of participants reaching TB disease/death by week 96 calculated using the Kaplan-Meier method.

Time From Randomization to Development of TB Infection or Death Among Perinatally Exposed, HIV-uninfected Children

Criteria for diagnosis with TB infection were outlined in the protocol. TB infection included TB disease (see primary outcome measure 1 for definition) and latent TB infection. Latent TB infection was diagnosed by a positive tuberculin skin test (TST) based on a purified protein derivative (PPD) performed at week 96. Participant records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB infection. Results report percent of participants reaching TB infection or death by week 96 calculated using the Kaplan-Meier method.

Secondary Outcome Measures

Time From Randomization to Development of TB Infection or Death Among HIV-infected Children

Criteria for diagnosis with TB infection were outlined in the protocol. TB infection included TB disease (see primary outcome measure 1 for definition) and latent TB infection. Latent TB infection was diagnosed by a positive TST based on a PPD performed at week 96. Participant records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB infection. Results report percent of participants reaching TB infection or death by week 96 calculated using the Kaplan-Meier method.

Time From Randomization to HIV Disease Progression or Death Among HIV-infected Children

HIV disease progression was defined as any advancement in Centers for Disease Control (CDC) disease category from entry or death. If a participant was CDC disease category C at entry progression was defined as death. Results report percent of participants with HIV progression or death by week 96 calculated using the Kaplan-Meier method.

Time From Randomization to Development of TB Disease or Death Among Perinatally Exposed, HIV-uninfected Children

Criteria for diagnosis with TB disease were: Definite-isolation of M.tb or positive stain on CSF; Probable-positive AFB stain on fluids/tissues other than CSF and sufficient clinical criteria/radiographic evidence suggestive of TB; Possible-abnormal chest radiograph suggestive of PTB and either a +ve TST or minimum score on algorithm to diagnose clinical TB. All records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB disease. Results report percent of participants reaching TB disease/death by week 96 calculated using the Kaplan-Meier method.

Time From Randomization to Development of TB Disease Among HIV Infected and Perinatally Exposed, HIV-uninfected Children

Time From Randomization to Development of TB Infection Among HIV-infected and Perinatally Exposed, HIV-uninfected Children

Criteria for diagnosis with TB infection were outlined in the protocol. TB infection included TB disease (see primary outcome measure 1 for definition) and latent TB infection. Latent TB infection was diagnosed by a positive TST based on a PPD performed at week 96. Participant records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB infection. Results report percent of participants reaching TB infection by week 96 calculated using the Kaplan-Meier method.

Time From Randomization to Death Among HIV-infected and Perinatally Exposed, HIV-uninfected Children

Deaths from any cause were included. Results report percent of participants dying by week 96 calculated using the Kaplan-Meier method.

Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children

Signs, symptoms and laboratory values were graded according to the Division of AIDS Adverse Event Grading System. Any event of grade 3 or higher not present at entry that occurred after randomization was classified as a new event. Results report percent of participants with a new event by week 96 calculated using the Kaplan-Meier method.

Full Information

NCT ID

NCT00080119

First Posted

March 23, 2004

Last Updated

January 17, 2019

Sponsor

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID), Comprehensive International Program of Research on AIDS, Secure the Future Foundation

1. Study Identification

Unique Protocol Identification Number

NCT00080119

Brief Title

Daily Isoniazid to Prevent Tuberculosis in Infants Born to Mothers With HIV

Official Title

A Randomized, Double Blind, Placebo Controlled Trial to Determine the Efficacy of Isoniazid (INH) in Preventing Tuberculosis Disease and Latent Tuberculosis Infection Among Infants With Perinatal Exposure to HIV

Study Type

Interventional

2. Study Status

Record Verification Date

January 2019

Overall Recruitment Status

Terminated

Why Stopped

Data Safety Monitoring Board (DSMB) recommended stopping study due to futility

Study Start Date

February 2004 (undefined)

Primary Completion Date

May 2009 (Actual)

Study Completion Date

May 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID), Comprehensive International Program of Research on AIDS, Secure the Future Foundation

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Tuberculosis (TB) is highly endemic in sub-Saharan Africa. The increased burden of TB in settings with high prevalence of the Human Immunodeficiency Virus (HIV) is associated with high rates of transmission of Mycobacterium tuberculosis (M.tb) to both adults and children. Children infected with TB have a higher risk of developing severe disease than adults with TB. The purpose of this study was to determine if the antibiotic isoniazid (INH) prevented TB infection in infants born to HIV-infected mothers.

Detailed Description

Tuberculosis (TB) and the Human Immunodeficiency Virus (HIV) are major public health problems in southern Africa, and the incidence of TB in South Africa is among the highest in the world. TB is caused by the highly contagious bacterium Mycobacterium tuberculosis. The use of Isoniazid (INH) prophylaxis in adults has been associated with reduced risk of TB disease in high-risk populations. Delay in initiating INH prophylaxis in children has resulted in more cases of childhood TB infection. This study evaluated the effectiveness of INH prophylaxis in preventing TB infection in infants born to HIV-infected mothers in southern Africa. Infants were randomly assigned to receive either INH or placebo by mouth daily, beginning between the 91st and 120th day of life, and at least 90 days after Bacille Calmette-Guerin (BCG) vaccination. At sites in South Africa, HIV-infected infants received daily trimethoprim/sulfamethoxazole (TMP/SMX) as Pneumocystis jiroveci pneumonia (PCP) prophylaxis until at least 1 year of age; HIV-uninfected infants received TMP/SMX until at least 6 months of age. The study was to follow participants for 192 weeks. Study visits occurred at study entry and every 12 weeks until week 192. A physical exam and blood collection occurred at each study visit. Infants were assessed for peripheral neuropathy every 12 weeks until week 96 and for TB at weeks 96, 144, and 192. The study also assessed medication adherence. As of November 12, 2008, follow-up was revised. All participants were permanently discontinued from study follow-up by February 28, 2009 and no later than May 31, 2009. Only clinical evaluations were performed for all participants. For HIV-infected participants, the study drug was stopped at the next scheduled visit. For HIV-uninfected subjects, the study drug was discontinued immediately.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV Infection, Tuberculosis, Pneumocystis Jiroveci Pneumonia

Keywords

Treatment Naive, INH Prophylaxis, HIV Seronegativity

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

1354 (Actual)

8. Arms, Groups, and Interventions

Arm Title

HIVneg/INH

Arm Type

Experimental

Arm Description

Arm Title

HIVneg/PL

Arm Type

Placebo Comparator

Arm Description

Arm Title

HIVpos/INH

Arm Type

Experimental

Arm Description

Arm Title

HIVpos/PL

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Isoniazid (INH)

Intervention Description

Antibiotic for the prevention and treatment of TB

Intervention Type

Drug

Intervention Name(s)

Trimethoprim/Sulfamethoxazole (TMP/SMX)

Intervention Description

Antibiotic for the prevention and treatment of pneumocystis pneumonia (PCP)

Intervention Type

Drug

Intervention Name(s)

Isoniazid Placebo (PL)

Intervention Description

Isoniazid placebo and TMP/SMX

Primary Outcome Measure Information:

Title

Time to Development of Tuberculosis (TB) Disease or Death Among HIV-infected Children

Description

Time Frame

Through to week 96

Title

Time From Randomization to Development of TB Infection or Death Among Perinatally Exposed, HIV-uninfected Children

Description

Time Frame

Through to week 96

Secondary Outcome Measure Information:

Title

Time From Randomization to Development of TB Infection or Death Among HIV-infected Children

Description

Criteria for diagnosis with TB infection were outlined in the protocol. TB infection included TB disease (see primary outcome measure 1 for definition) and latent TB infection. Latent TB infection was diagnosed by a positive TST based on a PPD performed at week 96. Participant records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB infection. Results report percent of participants reaching TB infection or death by week 96 calculated using the Kaplan-Meier method.

Time Frame

Through to week 96

Title

Time From Randomization to HIV Disease Progression or Death Among HIV-infected Children

Description

Time Frame

Through to week 96

Title

Time From Randomization to Development of TB Disease or Death Among Perinatally Exposed, HIV-uninfected Children

Description

Time Frame

Through to week 96

Title

Time From Randomization to Development of TB Disease Among HIV Infected and Perinatally Exposed, HIV-uninfected Children

Description

Time Frame

Through to week 96

Title

Time From Randomization to Development of TB Infection Among HIV-infected and Perinatally Exposed, HIV-uninfected Children

Description

Criteria for diagnosis with TB infection were outlined in the protocol. TB infection included TB disease (see primary outcome measure 1 for definition) and latent TB infection. Latent TB infection was diagnosed by a positive TST based on a PPD performed at week 96. Participant records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB infection. Results report percent of participants reaching TB infection by week 96 calculated using the Kaplan-Meier method.

Time Frame

Through to week 96

Title

Time From Randomization to Death Among HIV-infected and Perinatally Exposed, HIV-uninfected Children

Description

Deaths from any cause were included. Results report percent of participants dying by week 96 calculated using the Kaplan-Meier method.

Time Frame

Through to week 96

Title

Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children

Description

Time Frame

Through to week 96

10. Eligibility

Sex

All

Minimum Age & Unit of Time

91 Days

Maximum Age & Unit of Time

120 Days

Accepts Healthy Volunteers

Eligibility Criteria

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Shabir Madhi, MD

Organizational Affiliation

University of Witwatersrand, South Africa

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

George McSherry, MD

Organizational Affiliation

UMDNJ - New Jersey Medical School

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Charles D. Mitchell, MD

Organizational Affiliation

University of Miami

Official's Role

Study Chair

Facility Information:

Facility Name

Princess Marina Hospital

City

Gaborone

Country

Botswana

Facility Name

University of Cape Town, Red Cross Children's Hospital

City

Cape Town

Country

South Africa

Facility Name

University of Stellenbosch, Tygerberg Hospital

City

Cape Town

Country

South Africa

Facility Name

Nelson R. Mandela School of Medicine, University of KwaZulu Natal, Durban

City

Durban

ZIP/Postal Code

4001

Country

South Africa

Facility Name

Perinatal HIV Research Unit at Chris Hani Baragwanath Hospital

City

Johannesburg

ZIP/Postal Code

2013

Country

South Africa

Facility Name

Chris Hani Baragwanath Hospital, Harriet Shezi Clinic

City

Johannesburg

Country

South Africa

12. IPD Sharing Statement

Citations:

PubMed Identifier

15875917

Citation

Chintu C, Mwaba P. Tuberculosis in children with human immunodeficiency virus infection. Int J Tuberc Lung Dis. 2005 May;9(5):477-84.

Results Reference

background

PubMed Identifier

12742798

Citation

Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med. 2003 May 12;163(9):1009-21. doi: 10.1001/archinte.163.9.1009.

Results Reference

background

PubMed Identifier

14746522

Citation

de Jong BC, Israelski DM, Corbett EL, Small PM. Clinical management of tuberculosis in the context of HIV infection. Annu Rev Med. 2004;55:283-301. doi: 10.1146/annurev.med.55.091902.103753.

Results Reference

background

PubMed Identifier

14551885

Citation

Toossi Z. Virological and immunological impact of tuberculosis on human immunodeficiency virus type 1 disease. J Infect Dis. 2003 Oct 15;188(8):1146-55. doi: 10.1086/378676. Epub 2003 Sep 30.

Results Reference

background

PubMed Identifier

18230259

Citation

Cotton MF, Schaaf HS, Lottering G, Weber HL, Coetzee J, Nachman S; PACTG 1041 Team. Tuberculosis exposure in HIV-exposed infants in a high-prevalence setting. Int J Tuberc Lung Dis. 2008 Feb;12(2):225-7.

Results Reference

result

PubMed Identifier

20607114

Citation

Cotton M, Kim S, Rabie H, Coetzee J, Nachman S. A window into a public program for prevention of mother to child transmission of HIV: evidence from a prospective clinical trial. South Afr J HIV Med. 2009 Jan 1;10(4):16-19. doi: 10.4102/sajhivmed.v10i4.257.

Results Reference

result

PubMed Identifier

26872154

Citation

Gupta A, Montepiedra G, Gupte A, Zeldow B, Jubulis J, Detrick B, Violari A, Madhi S, Bobat R, Cotton M, Mitchell C, Spector S; IMPAACT NWCS113 and P1041 Study Team. Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants. PLoS One. 2016 Feb 12;11(2):e0148649. doi: 10.1371/journal.pone.0148649. eCollection 2016.

Results Reference

derived

PubMed Identifier

21732834

Citation

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.

Results Reference

derived

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Daily Isoniazid to Prevent Tuberculosis in Infants Born to Mothers With HIV

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