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| ID | Type | Description | Link |
|---|---|---|---|
| U01AI068632 | U.S. NIH Grant/Contract | View source |
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Data Safety Monitoring Board (DSMB) recommended stopping study due to futility
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| Name | Class |
|---|---|
| National Institute of Allergy and Infectious Diseases (NIAID) | NIH |
| Comprehensive International Program of Research on AIDS | OTHER |
| Secure the Future Foundation | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| HIVneg/INH | Experimental | 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 |
|
| HIVneg/PL | Placebo Comparator | 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 |
|
| HIVpos/INH | Experimental | 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. |
|
| HIVpos/PL | Placebo Comparator | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Isoniazid (INH) | Drug | Antibiotic for the prevention and treatment of TB |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Through to week 96 |
| 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. | Through to week 96 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Shabir Madhi, MD | University of Witwatersrand, South Africa | Study Chair |
| George McSherry, MD | UMDNJ - New Jersey Medical School | Study Chair |
| Charles D. Mitchell, MD | University of Miami | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Princess Marina Hospital | Gaborone | Botswana | ||||
| University of Cape Town, Red Cross Children's Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 15875917 | Background | Chintu C, Mwaba P. Tuberculosis in children with human immunodeficiency virus infection. Int J Tuberc Lung Dis. 2005 May;9(5):477-84. | |
| 12742798 | Background | 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. |
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Infants perinatally exposed to HIV 91-120 days with documented receipt of Bacille Calmette-Guerin (BCG) vaccine by 30 days (>=90 days since receipt), no previous diagnosis or treatment of TB or contact with known TB case, stratified by HIV and randomized to receive blinded INH or INH placebo. 3 participants randomized but did not start treatment.
Study participants were recruited at four study sites, three in South Africa and one in Botswana, between December 13, 2004 and June 26, 2008
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| ID | Title | Description |
|---|---|---|
| FG000 | HIVneg/INH | 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 |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Trimethoprim/Sulfamethoxazole (TMP/SMX) | Drug | Antibiotic for the prevention and treatment of pneumocystis pneumonia (PCP) |
|
| Isoniazid Placebo (PL) | Drug | Isoniazid placebo and TMP/SMX |
|
| Through to week 96 |
| 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. | Through to week 96 |
| 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. | Through to week 96 |
| Time From Randomization to Development of TB Disease Among HIV Infected and 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. | Through to week 96 |
| 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. | Through to week 96 |
| 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. | Through to week 96 |
| 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. | Through to week 96 |
| Cape Town |
| South Africa |
| University of Stellenbosch, Tygerberg Hospital | Cape Town | South Africa |
| Nelson R. Mandela School of Medicine, University of KwaZulu Natal, Durban | Durban | 4001 | South Africa |
| Perinatal HIV Research Unit at Chris Hani Baragwanath Hospital | Johannesburg | 2013 | South Africa |
| Chris Hani Baragwanath Hospital, Harriet Shezi Clinic | Johannesburg | South Africa |
| 14746522 | Background | 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. |
| 14551885 | Background | 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. |
| 18230259 | Result | 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. |
| 20607114 | Result | 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. |
| 26872154 | Derived | 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. |
| 21732834 | Derived | 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. |
| HIVneg/PL |
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 |
| FG002 | HIVpos/INH | 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. |
| FG003 | HIVpos/PL | 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. |
| COMPLETED |
|
| NOT COMPLETED |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | HIVneg/INH | 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 |
| BG001 | HIVneg/PL | 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 |
| BG002 | HIVpos/INH | 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. |
| BG003 | HIVpos/PL | 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. |
| BG004 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Number | participants |
| ||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Number | participants |
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| Age at receipt of Bacille Calmette-Guerin (BCG) vaccination (days) | Number | participants |
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| Any smoker in household | Number | participants |
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| Birth weight (grams) | Number | participants |
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| CD4% | Only for HIV-infected participants. Those in the HIV-infected stratum that were later determined to be HIV-uninfected are recorded as not applicable. | Number | participants |
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| Centers for Disease Control (CDC) Disease Category | Only for HIV-infected participants. | Number | participants |
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| Caregiver currently smokes | Number | participants |
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| Ever breastfed | Number | participants |
| ||||||||||||||||
| HIV-1 RNA (copies/ml) | Only for HIV-infected participants. Those in the HIV-infected stratum that were later determined to be HIV-uninfected are recorded as not applicable. | Number | participants |
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| History of tuberculosis (TB) in mother | Number | participants |
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| Housing | Number | participants |
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| On antiretrovirals at entry | Only for HIV-infected participants. Those in the HIV-infected stratum that were later determined to be HIV-uninfected are recorded as not applicable. | Number | participants |
| |||||||||||||||
| Site of enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Includes HIVpos who started study treatment. Time from randomization to TB disease/death was calculated. Participants lost-to-follow-up (LTF) <96 wks (+12wks) censored at the time of LTF. Participants in follow-up at 96 wks free of TB disease censored at 96 wks. Participants on study when study discontinued censored at discontinuation visit. | Posted | Number | Percent of participants | Through to week 96 |
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| Primary | 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. | HIVneg who started study treatment were included. Time from randomization to first of TB infection/death was calculated. Participants lost-to-follow-up before 96 wks were censored at the time of loss-to-follow-up. Participants in follow-up at 96 weeks (+12 week window) who were free of TB infection were censored at 96 weeks (+12 week window). | Posted | Number | Percent of participants | Through to week 96 |
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| Secondary | 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. | HIVpos starting study treatment were included. Time from randomization to first of TB infection/death was calculated. Participants LTF <96 weeks (+12 wk) censored at the time LTF. Participants in follow-up at 96 wks free of TB infection censored at 96 wks. Participants on study when study discontinued were censored at discontinuation visit. | Posted | Number | Percent of participants | Through to week 96 |
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| Secondary | 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. | Includes HIVpos starting study treatment. Time from randomization to first of disease progression/death calculated. Censored if LTF <96 wks, at 96 wks (if on study) or at discontinuation visit. Participants found to be HIVneg upon repeat testing could only progress by meeting a death endpoint. | Posted | Number | Percent of participants | Through to week 96 |
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| Secondary | 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. | Includes HIVneg who started study treatment. Time from randomization to the first of TB disease/death was calculated. Participants lost-to-follow-up before 96 weeks (+12 week window)were censored at the time of loss-to-follow-up. Participants in follow-up at 96 weeks who were free of TB disease were censored at 96 weeks (+12 week window). | Posted | Number | Percent of participants | Through to week 96 |
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| Secondary | Time From Randomization to Development of TB Disease Among HIV Infected and 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. | Includes all starting study treatment. Time from randomization to development of TB disease was calculated. Participants LTF <96 wks (+12 wks) censored at time of LTF. Participants in follow-up at 96 wks free of TB disease censored at 96 wks. HIVpos on study when study discontinued were censored at their discontinuation visit. | Posted | Number | Percent of participants | Through to week 96 |
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| Secondary | 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. | Includes all starting study treatment. Time from randomization to development of TB infection was calculated. Participants LTF <96 weeks (+12 wks) censored at the time of LTF. Participants in follow-up at 96 wks free of TB infection were censored at 96 wks. HIVpos on study when study discontinued censored at their discontinuation visit. | Posted | Number | Percent of participants | Through to week 96 |
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| Secondary | 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. | Includes all starting study treatment. Time from randomization to death was calculated. Participants LTF <96 weeks (+12 wks) censored at the time of LTF. Participants in follow-up at 96 wks (+12 wks) censored at 96 weeks. HIVpos on study when study was discontinued were censored at their discontinuation visit. | Posted | Number | Percent of participants | Through to week 96 |
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| Secondary | 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. | Includes all starting treatment. Time from randomization to first new adverse event (AE) calculated. For lab toxicities, censored at visit following permanent discontinuation of study drugs. For signs/symptoms, participants in follow-up at 96 wks (+12) with no new grade >=3 AE censored at 96 wks. Participants LTF <96 wks censored at LTF. | Posted | Number | Percent of participants | Through to week 96 |
|
From study enrollment until study completion and before May 25, 2009 (primary completion date)
Expedited adverse event (AE) reporting followed Intensive Division of AIDS (DAIDS) Reporting Level, which included AEs resulting in death, congenital anomalies, fetal losses, significant disabilities, requiring hospitalization, and >=grade 3 AEs defined by the "DAIDS Table for Grading the Severity of Adult and Pediatric AEs", V1.0, 12/2004.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | HIVneg/INH | 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 | 25 | 403 | 353 | 403 | ||
| EG001 | HIVneg/PL | 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 | 18 | 401 | 368 | 401 | ||
| EG002 | HIVpos/INH | 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. | 55 | 273 | 264 | 273 | ||
| EG003 | HIVpos/PL | 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. | 42 | 274 | 268 | 274 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Neutropenia | Blood and lymphatic system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Pancytopenia | Blood and lymphatic system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Cardiac failure | Cardiac disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Visual acuity reduced | Eye disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Accidental death | General disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Death | General disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Sudden infant death syndrome | General disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Hepatic failure | Hepatobiliary disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Hepatotoxicity | Hepatobiliary disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Bronchiolitis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Bronchopneumonia | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Encephalitis viral | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Escherichia sepsis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Gastroenteritis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| HIV infection | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Infection | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Lobar pneumonia | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Pneumonia | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Pneumonia cytomegaloviral | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Pneumonia herpes viral | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Pneumonia necrotising | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Sepsis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Tuberculosis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Tuberculosis of eye | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Drug toxicity | Injury, poisoning and procedural complications | MedDRA (12.1) | Systematic Assessment |
| |
| Poisoning | Injury, poisoning and procedural complications | MedDRA (12.1) | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | MedDRA (12.1) | Systematic Assessment |
| |
| Aspartate aminotransferase increased | Investigations | MedDRA (12.1) | Systematic Assessment |
| |
| Haemoglobin decreased | Investigations | MedDRA (12.1) | Systematic Assessment |
| |
| Liver function test abnormal | Investigations | MedDRA (12.1) | Systematic Assessment |
| |
| Neutrophil count decreased | Investigations | MedDRA (12.1) | Systematic Assessment |
| |
| Transaminases increased | Investigations | MedDRA (12.1) | Systematic Assessment |
| |
| Failure to thrive | Metabolism and nutrition disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Encephalopathy | Nervous system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Neuropathy peripheral | Nervous system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Status epilepticus | Nervous system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Aspiration | Respiratory, thoracic and mediastinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Erythema multiforme | Skin and subcutaneous tissue disorders | MedDRA (12.1) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lymphadenitis | Blood and lymphatic system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA (12.1) | Systematic Assessment |
| |
| AIDS encephalopathy | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Acarodermatitis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Bronchiolitis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Bronchitis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Gastroenteritis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Oral candidiasis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Otitis media acute | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Pharyngitis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Pneumonia | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Pulmonary tuberculosis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Tonsilitis | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Upper respiratory tract infection | Infections and infestations | MedDRA (12.1) | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | MedDRA (12.1) | Systematic Assessment |
| |
| Aspartate aminotransferase increased | Investigations | MedDRA (12.1) | Systematic Assessment |
| |
| Gamma-glutamyltransferase increased | Investigations | MedDRA (12.1) | Systematic Assessment |
| |
| Haemoglobin decreased | Investigations | MedDRA (12.1) | Systematic Assessment |
| |
| Neutrophil count decreased | Investigations | MedDRA (12.1) | Systematic Assessment |
| |
| Failure to thrive | Metabolism and nutrition disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Neuropathy peripheral | Nervous system disorders | MedDRA (12.1) | Systematic Assessment |
| |
| Eczema | Skin and subcutaneous tissue disorders | MedDRA (12.1) | Systematic Assessment |
|
DSMB recommended stopping study due to futility: "no compelling reason to enroll additional infants" or "to continue to treat participants with the blinded study medication". Week 192 analyses not done as <4% (26%) of HIVpos (HIVneg) reached wk 192
In accordance with the Clinical Trial Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Melissa Allen, Director, IMPAACT Operations Center | Family Health International (FHI 360) | (919) 405-1429 | mallen@fhi360.org |
| ID | Term |
|---|---|
| D015658 | HIV Infections |
| D014376 | Tuberculosis |
| D011020 | Pneumonia, Pneumocystis |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D015229 | Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D008172 | Lung Diseases, Fungal |
| D009181 | Mycoses |
| D016720 | Pneumocystis Infections |
| D012141 | Respiratory Tract Infections |
| D011014 | Pneumonia |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D007538 | Isoniazid |
| D014295 | Trimethoprim |
| D013420 | Sulfamethoxazole |
| D015662 | Trimethoprim, Sulfamethoxazole Drug Combination |
| ID | Term |
|---|---|
| D006834 | Hydrazines |
| D009930 | Organic Chemicals |
| D007539 | Isonicotinic Acids |
| D000147 | Acids, Heterocyclic |
| D006571 | Heterocyclic Compounds |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D011743 | Pyrimidines |
| D000096926 | Benzenesulfonamides |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D013424 | Sulfanilamides |
| D000814 | Aniline Compounds |
| D000588 | Amines |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |
Not provided
Not provided
| 101-110 days |
|
| 111-120 days |
|
| Male |
|
| Mixed ancestry/other |
|
| 8-29 days |
|
| No |
|
| Missing |
|
| >= 2500 grams |
|
| 20%-<25% |
|
| >= 25% |
|
| Missing |
|
| Not applicable |
|
| Category B |
|
| Category C |
|
| HIV-uninfected on repeat test |
|
| Missing |
|
| Not applicable (HIV-uninfected) |
|
| No |
|
| No |
|
| 401 - <20,000 copies/ml |
|
| 20,000 - < 750,000 copies/ml |
|
| >= 750,000 copies/ml |
|
| Missing |
|
| Not applicable |
|
| No |
|
| Informal (shack/wooden) |
|
| Hostel |
|
| Missing |
|
| No |
|
| Not applicable |
|
| Cape Town, S Africa |
|
| Durban, S Africa |
|
| Gaborone, Botswana |
|
|
|
|
|
|
|
|
|
|
|
|
| Units | Counts |
|---|
| Participants |
|
|