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

This study has been terminated.

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

Study NCT00080119 Information provided by International Maternal Pediatric Adolescent AIDS Clinical Trials Group

First Received on March 23, 2004. Last Updated on February 10, 2011 History of Changes

Results First Received: July 1, 2010

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator); Primary Purpose: Prevention
Conditions:	HIV Infection Tuberculosis Pneumocystis Jiroveci Pneumonia
Interventions:	Drug: Isoniazid (INH) Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX) Drug: Isoniazid Placebo (PL)

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Study participants were recruited at four study sites, three in South Africa and one in Botswana, between December 13, 2004 and June 26, 2008

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
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
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
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.
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.

Participant Flow: Overall Study

	HIVneg/INH	HIVneg/PL	HIVpos/INH	HIVpos/PL
STARTED	403	401	273	274
COMPLETED	347	339	108	111
NOT COMPLETED	56	62	165	163
Discontinued because of study closure	0	0	130	141
Unable to get to clinic	24	24	7	1
Consent withdrawn	13	17	4	6
Unwilling to adhere to study requirement	3	2	5	1
Lost to Follow-up	16	19	19	14

Baseline Characteristics

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Reporting Groups

	Description
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
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
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.
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.

Baseline Measures

	HIVneg/INH	HIVneg/PL	HIVpos/INH	HIVpos/PL	Total
Number of Participants [units: participants]	403	401	273	274	1351
Age, Customized [units: participants]
91-100 days	258	253	171	192	874
101-110 days	71	84	56	33	244
111-120 days	74	64	46	49	233
Gender [units: participants]
Female	203	190	159	151	703
Male	200	211	114	123	648
Race/Ethnicity, Customized [units: participants]
Indigenous African	389	386	264	272	1311
Mixed ancestry/other	14	15	9	2	40
Age at receipt of Bacille Calmette-Guerin (BCG) vaccination (days) [units: participants]
<= 7 days	395	392	255	258	1300
8-29 days	8	9	18	16	51
Any smoker in household [units: participants]
Yes	191	177	120	131	619
No	211	224	153	141	729
Missing	1	0	0	2	3
Birth weight (grams) [units: participants]
<2500 grams	49	49	68	56	222
>= 2500 grams	354	352	205	218	1129
CD4% ^[1] [units: participants]
<20%	0	0	56	55	111
20%-<25%	0	0	40	46	86
>= 25%	0	0	162	157	319
Missing	0	0	14	13	27
Not applicable	403	401	1	3	808
Centers for Disease Control (CDC) Disease Category ^[2] [units: participants]
Category N or A	0	0	252	244	496
Category B	0	0	16	21	37
Category C	0	0	2	3	5
HIV-uninfected on repeat test	0	0	1	3	4
Missing	0	0	2	3	5
Not applicable (HIV-uninfected)	403	401	0	0	804
Caregiver currently smokes [units: participants]
Yes	11	25	16	10	62
No	392	376	257	264	1289
Ever breastfed [units: participants]
Yes	24	24	37	36	121
No	379	377	236	238	1230
HIV-1 RNA (copies/ml) ^[1] [units: participants]
<= 400 copies/ml	0	0	8	12	20
401 - <20,000 copies/ml	0	0	36	51	87
20,000 - < 750,000 copies/ml	0	0	91	86	177
>= 750,000 copies/ml	0	0	129	116	245
Missing	0	0	8	6	14
Not applicable	403	401	1	3	808
History of tuberculosis (TB) in mother [units: participants]
Yes	33	25	14	25	97
No	370	376	259	249	1254
Housing [units: participants]
Formal (brick) house	235	233	162	183	813
Informal (shack/wooden)	168	168	109	89	534
Hostel	0	0	2	0	2
Missing	0	0	0	2	2
On antiretrovirals at entry ^[3] [units: participants]
Yes	0	0	78	93	171
No	0	0	194	178	372
Not applicable	403	401	1	3	808
Site of enrollment [units: participants]
Johannesburg, S Africa	259	260	180	179	878
Cape Town, S Africa	140	138	66	65	409
Durban, S Africa	4	3	26	27	60
Gaborone, Botswana	0	0	1	3	4

[1]	Only for HIV-infected participants. Those in the HIV-infected stratum that were later determined to be HIV-uninfected are recorded as not applicable.
[2]	Only for HIV-infected participants.
[3]	Only for HIV-infected participants. Those in the HIV-infected stratum that were later determined to be HIV-uninfected are recorded as not applicable.

Outcome Measures

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1. Primary:

Time to Development of Tuberculosis (TB) Disease or Death Among HIV-infected Children [ Time Frame: Through to week 96 ]

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2. Primary:

Time From Randomization to Development of TB Infection or Death Among Perinatally Exposed, HIV-uninfected Children [ Time Frame: Through to week 96 ]

Show Outcome Measure 2

3. Secondary:

Time From Randomization to Development of TB Infection or Death Among HIV-infected Children [ Time Frame: Through to week 96 ]

Show Outcome Measure 3

4. Secondary:

Time From Randomization to HIV Disease Progression or Death Among HIV-infected Children [ Time Frame: Through to week 96 ]

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5. Secondary:

Time From Randomization to Development of TB Disease or Death Among Perinatally Exposed, HIV-uninfected Children [ Time Frame: Through to week 96 ]

Show Outcome Measure 5

6. Secondary:

Time From Randomization to Development of TB Disease Among HIV Infected and Perinatally Exposed, HIV-uninfected Children [ Time Frame: Through to week 96 ]

Show Outcome Measure 6

7. Secondary:

Time From Randomization to Development of TB Infection Among HIV-infected and Perinatally Exposed, HIV-uninfected Children [ Time Frame: Through to week 96 ]

Show Outcome Measure 7

8. Secondary:

Time From Randomization to Death Among HIV-infected and Perinatally Exposed, HIV-uninfected Children [ Time Frame: Through to week 96 ]

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9. Secondary:

Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children [ Time Frame: Through to week 96 ]

Show Outcome Measure 9

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There IS 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.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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

Results Point of Contact:

Name/Title: Clinicaltrials.gov Coordinator
Organization: Center for Biostatistics in AIDS Research, Harvard School of Public Health
phone: (617) 432-2829
e-mail: CBAR.ClinicalTrials.Gov@sdac.harvard.edu

Publications of Results:

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.

Cotton M, Kim S, Rabie H, Coetzee J, Nachman S for the PACTG 1041 Team. A window into a public program for prevention of mother to child transmission of HIV: evidence from a prospective clinical trial. The Southern African Journal of HIV Medicine 10(4): 16-19, 2009.

Other Publications:

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

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. Review.

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.

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. Epub 2003 Sep 30. Review.

Publications automatically indexed to this study:

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.

Responsible Party:	Wende Levy, IMPAACT
ClinicalTrials.gov Identifier:	NCT00080119 History of Changes
Other Study ID Numbers:	PACTG P1041, U01AI068632
Study First Received:	March 23, 2004
Results First Received:	July 1, 2010
Last Updated:	February 10, 2011
Health Authority:	United States: Federal Government